Louanne Hudgins

Abstract

The objective of our study was to describe the clinical experience in offering noninvasive prenatal testing (NIPT) for aneuploidy to pregnant patients, highlighting the clinical utility, barriers to acceptance and limitations of this novel test. Data were collected from 961 patients offered NIPT from 3/1/12 to 9/30/12. Univariate and multivariate logistic regression analysis was performed. Twenty-eight percent of patients elected NIPT and 72 % declined. Women continue to elect less sensitive and less specific screening through biochemical markers and nuchal translucency. Women considering all options at average risk for aneuploidy were less likely to accept NIPT testing than women who had a risk adjustment from an ultrasound marker or routine screening test. In our multi-ethnic population, Filipina women were significantly less likely to elect NIPT compared to other ethnicities. Five percent of NIPT ordered failed analysis. Several chromosome abnormalities were detected through CVS or amniocentesis that would not have been detected by NIPT. Even though NIPT offers a non-invasive, highly sensitive and specific analysis for aneuploidy, the majority of women in our study declined this option. NIPT should be offered in the context of genetic counseling so that women understand the limitations of the testing and make an educated decision about the testing option best suited to their situation.

View details for DOI 10.1007/s10897-013-9609-z

View details for PubMedID 23723049

Abstract

Cornelia de Lange syndrome (CdLS) is a multisystem genetic disorder with distinct facies, growth failure, intellectual disability, distal limb anomalies, gastrointestinal and neurological disease. Mutations in NIPBL, encoding a cohesin regulatory protein, account for more than 80% of cases with typical facies. Mutations in the core cohesin complex proteins, encoded by the SMC1A, SMC3 and RAD21 genes, together account for ∼5% of subjects, often with atypical CdLS features. Recently, we identified mutations in the X-linked gene HDAC8 as the cause of a small number of CdLS cases. Here we report a cohort of 35 individuals with an emerging spectrum of features caused by HDAC8 mutations. For several individuals, the diagnosis of CdLS was not considered prior to genomic testing. Most mutations identified are missense and de novo. Many cases are heterozygous females, each with marked skewing of X-inactivation in peripheral blood DNA. We also identified eight hemizygous males who are more severely affected. The craniofacial appearance caused by HDAC8 mutations overlaps that of typical CdLS but often displays delayed anterior fontanelle closure, ocular hypertelorism, hooding of the eyelids, a broader nose and dental anomalies, which may be useful discriminating features. HDAC8 encodes the lysine deacetylase for the cohesin subunit SMC3 and analysis of the functional consequences of the missense mutations indicates that all cause a loss of enzymatic function. These data demonstrate that loss of function mutations in HDAC8 cause a range of overlapping human developmental phenotypes, including a phenotypically distinct subgroup of CdLS.

View details for DOI 10.1093/hmg/ddu002

View details for PubMedID 24403048

Abstract

Background:Clinical laboratories began offering whole-exome sequencing in 2011 at a cost between $4,500 and $9,000. Reported detection rates for deleterious mutations range from 25 to 50%. Based on the experience of our clinical genetics service, actual success rates may be lower than estimated rates. We report results from our own experience along with a survey of clinical geneticists to ascertain (i) current success rates for causal gene detection in a clinical setting; (ii) if there are insurance authorization issues; and (iii) if turnaround times quoted by the clinical laboratories are accurate; we also gauge provider opinions toward clinical whole-exome sequencing.Methods:We reviewed our results and the results of a survey that was electronically distributed to 47 clinical genetics centers.Results:A total of 35 exome reports were available. If all positive results are collated, we observe a success rate of 22.8%. One result incorrectly identified a known benign variant as pathogenic. Some insurers covered all testing, whereas others denied any insurance coverage. Only three (23.1%) of our reports were available within the laboratory's quoted turnaround times. More than 50% of clinicians queried in our survey had not ordered whole-exome sequencing at the current time, many stating concerns regarding interpretation, insurance coverage, and cost.Conclusion:Clinical whole-exome sequencing has proven diagnostic utility; however, currently many clinicians have concerns regarding interpretation of results, insurance coverage, and cost.Genet Med advance online publication 13 February 2014Genetics in Medicine (2014); doi:10.1038/gim.2014.10.

View details for DOI 10.1038/gim.2014.10

View details for PubMedID 24525916

Abstract

The TARP syndrome (Talipes equinovarus, Atrial septal defect, Robin sequence, and Persistent left superior vena cava) is an X-linked disorder that was determined to be caused by mutations in RBM10 in two families, and confirmed in a subsequent case report. The first two original families were quite similar in phenotype, with uniform early lethality although a confirmatory case report showed survival into childhood. Here we report on five affecteds from three newly recognized families, including patients with atypical manifestations. None of the five patients had talipes and others also lacked cardinal TARP features of Robin sequence and atrial septal defect. All three families demonstrated de novo mutations, and one of the families had two recurrences, with demonstrable maternal mosaicism. © 2013 Wiley Periodicals, Inc.

View details for DOI 10.1002/ajmg.a.36212

View details for PubMedID 24259342

Abstract

Noninvasive prenatal testing (NIPT) allows for highly sensitive detection of Down syndrome early in pregnancy with no risk of miscarriage, therefore potentially increasing the number of pregnancies identified with Down syndrome. This study assesses how mothers of children with Down syndrome perceive NIPT, especially the impact they think it will have on their families and other families with children who have Down syndrome. Seventy-three self-reported mothers of children with Down syndrome responded to an anonymous online survey emailed to, and posted on, message boards of various Down syndrome support groups and networks. Data analysis included chi-square tests and thematic analysis. Fifty-nine percent of respondents indicated they would use NIPT in the future; respondents who had not used prenatal testing in the past were significantly less likely to report interest in using NIPT in the future than those who had prenatal testing previously (p < .001). Many respondents felt NIPT could lead to increased terminations (88 %), increased social stigma (57 %), and decreased availability of services for individuals with Down syndrome (64 %). However, only 16 % believed availability of new noninvasive tests would be the most important factor in determining the number of pregnancies with Down syndrome terminated in the future. Additionally, 48 % believed health care providers give biased or incorrect information about Down syndrome at the time of diagnosis, and 24 % felt this incorrect information leads to terminations of pregnancies affected with Down syndrome. Results suggest although mothers of children with Down syndrome believe new noninvasive testing will lead to an increase in termination of pregnancies with Down syndrome, they do not think it is the MOST important factor. They also highlight the need to provide a diagnosis of Down syndrome in a balanced and objective manner.

View details for DOI 10.1007/s10897-014-9694-7

View details for PubMedID 24481673

Abstract

Purpose:Prenatal diagnosis of fetal Mendelian disorders can benefit from noninvasive approaches using fetal cell-free DNA in maternal plasma. Detecting metabolic disorders before birth can result in immediate treatment postpartum in order to optimize outcome.Methods:We developed a mathematical model and an experimental methodology to analyze the case of a fetus with a 25% risk of inheriting two known mutations in MUT that cause methylmalonic acidemia. To accomplish this, we measured allelic counts at the mutation sites and the fetal fraction from high minor-allele-frequency single-nucleotide polymorphism positions.Results:By counting linked alleles, the test was able to distinguish 11 positive markers from the negative controls and thereby determine whether or not the mutations carried by the parents were inherited by the fetus. For a homozygous fetus, the Z-score of the mutation site was 5.97, whereas the median Z-score of all the linked alleles was 4.56 when all negative (heterozygous) controls had a Z-score <2.5.Conclusion:The application of this methodology for diagnosing methylmalonic acidemia shows that this is a cost-effective and noninvasive approach to diagnosing known mutations related to Mendelian disorders in the fetus.Genet Med advance online publication 9 January 2014Genetics in Medicine (2014); doi:10.1038/gim.2013.194.

View details for DOI 10.1038/gim.2013.194

View details for PubMedID 24406457

Abstract

OBJECTIVE: The goal of this study is to provide an ethical framework for clinicians and companies providing noninvasive prenatal testing using cell-free fetal DNA or whole fetal cells. METHOD: In collaboration with a National Institutes of Health-supported research ethics consultation committee together with feedback from an interdisciplinary group of clinicians, members of industry, legal experts, and genetic counselors, we developed a set of best practices for the provision of noninvasive prenatal genetic testing. RESULTS: Principal recommendations include the amendment of current informed consent procedures to include attention to the noninvasive nature of new testing and the potential for a broader range of results earlier in the pregnancy. We strongly recommend that tests should only be provided through licensed medical providers and not directly to consumers. CONCLUSION: Prenatal tests, including new methods using cell-free fetal DNA, are not currently regulated by government agencies, and limited professional guidance is available. In the absence of regulation, companies and clinicians should cooperate to adopt responsible best ethical practices in the provision of these tests. © 2013 John Wiley & Sons, Ltd.

View details for DOI 10.1002/pd.4144

View details for PubMedID 23613322

Abstract

We describe a newborn with a phenotype consistent with Adams-Oliver syndrome and truncus arteriosus. Although cardiovascular malformations associated with this syndrome have been previously published in the literature, this is the first description of truncus arteriosus in a patient with Adams-Oliver syndrome. We review other reports of Adams-Oliver syndrome previously described with cardiovascular malformations, consider possible genetic and embryologic mechanisms, and emphasize the need for cardiology consultation when a diagnosis of Adams-Oliver syndrome is suspected in the differential diagnosis. © 2013 Wiley Periodicals, Inc.

View details for DOI 10.1002/ajmg.a.35864

View details for Web of Science ID 000320649700021

Abstract

The objective of this study was to identify variables that may influence the decision to terminate or continue a pregnancy affected by a chromosome abnormality. We performed a retrospective cohort analysis of 286 pregnancies diagnosed with a chromosome abnormality following genetic counseling and prenatal diagnosis. Data obtained included procedure type, chromosome results, ethnicity, maternal age, use of fertility treatments, and uptake of genetic counseling after results, among other factors. Wilcoxon rank sum test, Fisher's exact test, and univariate and multivariate logistic regression models were used for data analysis. The overall termination rate in this study was 82.9 %. A lower likelihood to terminate was found in pregnancies with a diagnosis of a sex chromosome abnormality (OR 0.05, p?

View details for DOI 10.1007/s10897-012-9539-1

View details for Web of Science ID 000316291100008

View details for PubMedID 23001505

Abstract

In order to provide the best genetic counseling possible for women who learn of a diagnosis of Down syndrome prenatally, we sought to assess the timing of the decision to continue a pregnancy and the satisfaction these women had with learning this information. Fifty-six mothers of children with Down syndrome diagnosed prenatally between 2007 and 2010 completed a survey regarding their experience with decision-making after prenatal diagnosis. Approximately one third (17/56) of participants reported they knew before getting pregnant that they would not terminate for any reason, and almost half of the participants (24/56) reported they did not decide to continue their pregnancy until after the diagnosis. Many participants (82 %; 42/56) stated that learning the diagnosis during pregnancy increased their anxiety. The majority (88 %; 45/56) also reported that if they could do it over again, they would undergo prenatal testing for preparation purposes, despite increased anxiety. Religious and spiritual beliefs as well as feeling attached to the baby were the personal factors that had the greatest impact on most women's decision-making. Despite increased anxiety caused by learning the diagnosis prenatally, most women favored prenatal diagnosis as it allowed them time to process the information and prepare for the birth of their child.

View details for PubMedID 23604903

Abstract

Although biallelic mutations in non-collagen genes account for <10% of individuals with osteogenesis imperfecta, the characterization of these genes has identified new pathways and potential interventions that could benefit even those with mutations in type I collagen genes. We identified mutations in FKBP10, which encodes the 65 kDa prolyl cis-trans isomerase, FKBP65, in 38 members of 21 families with OI. These include 10 families from the Samoan Islands who share a founder mutation. Of the mutations, three are missense; the remainder either introduce premature termination codons or create frameshifts both of which result in mRNA instability. In four families missense mutations result in loss of most of the protein. The clinical effects of these mutations are short stature, a high incidence of joint contractures at birth and progressive scoliosis and fractures, but there is remarkable variability in phenotype even within families. The loss of the activity of FKBP65 has several effects: type I procollagen secretion is slightly delayed, the stabilization of the intact trimer is incomplete and there is diminished hydroxylation of the telopeptide lysyl residues involved in intermolecular cross-link formation in bone. The phenotype overlaps with that seen with mutations in PLOD2 (Bruck syndrome II), which encodes LH2, the enzyme that hydroxylates the telopeptide lysyl residues. These findings define a set of genes, FKBP10, PLOD2 and SERPINH1, that act during procollagen maturation to contribute to molecular stability and post-translational modification of type I procollagen, without which bone mass and quality are abnormal and fractures and contractures result.

View details for DOI 10.1093/hmg/dds371

View details for Web of Science ID 000312643400001

View details for PubMedID 22949511

Abstract

Fetal goiter may arise from a variety of etiologies including iodine deficiency, overtreatment of maternal Graves' disease, inappropriate maternal thyroid replacement and, rarely, congenital hypothyroidism. Fetal goiter is often associated with a retroflexed neck and polyhydramnios, raising concerns regarding airway obstruction in such cases. Prior reports have advocated for cordocentesis and intra-amniotic thyroid hormone therapy in order to confirm the diagnosis of fetal thyroid dysfunction, reduce the size of the fetal goiter, reduce polyhydramnios, aid with the assistance of maternal thyroid hormone therapy and reduce fetal malpresentation. We report two cases of conservatively managed fetal goiter, one resulting in a vaginal delivery, and no evidence of postnatal respiratory distress despite the presence of polyhydramnios and a retroflexed neck on prenatal ultrasound. © 2013 S. Karger AG, Basel.

View details for DOI 10.1159/000353387

View details for PubMedID 23920148

Abstract

As medical genetics has progressed from a descriptive entity to one focused on the functional relationship between genes and clinical disorders, emphasis has been placed on genomics. Genomics, a subelement of genetics, is the study of the genome, the sum total of all the genes of an organism. The human genome, which is contained in the 23 pairs of nuclear chromosomes and in the mitochondrial DNA of each cell, comprises >6 billion nucleotides of genetic code. There are some 23 000 protein-coding genes, a surprisingly small fraction of the total genetic material, with the remainder composed of noncoding DNA, regulatory sequences, and introns. The Human Genome Project, launched in 1990, produced a draft of the genome in 2001 and then a finished sequence in 2003, on the 50th anniversary of the initial publication of Watson and Crick's paper on the double-helical structure of DNA. Since then, this mass of genetic information has been translated at an ever-increasing pace into useable knowledge applicable to clinical medicine. The recent advent of massively parallel DNA sequencing (also known as shotgun, high-throughput, and next-generation sequencing) has brought whole-genome analysis into the clinic for the first time, and most of the current applications are directed at children with congenital conditions that are undiagnosable by using standard genetic tests for single-gene disorders. Thus, pediatricians must become familiar with this technology, what it can and cannot offer, and its technical and ethical challenges. Here, we address the concepts of human genomic analysis and its clinical applicability for primary care providers.

View details for DOI 10.1542/peds.2013-1032E

View details for PubMedID 24298129

Abstract

An emerging debate in academic medical centers is not about the need for providing trainees with fundamental education on genomics, but rather the most effective educational models that should be deployed. At Stanford School of Medicine, a novel hands-on genomics course was developed in 2010 that provided students the option to undergo personal genome testing as part of the course curriculum. We hypothesized that use of personal genome testing in the classroom would enhance the learning experience of students. No data currently exist on how such methods impact student learning; thus, we surveyed students before and after the course to determine its impact. We analyzed responses using paired statistics from the 31 medical and graduate students who completed both pre-course and post-course surveys. Participants were stratified by those who did (N = 23) or did not (N = 8) undergo personal genome testing. In reflecting on the experience, 83% of students who underwent testing stated that they were pleased with their decision compared to 12.5% of students who decided against testing (P = 0.00058). Seventy percent of those who underwent personal genome testing self-reported a better understanding of human genetics on the basis of having undergone testing. Further, students who underwent personal genome testing demonstrated an average 31% increase in pre- to post-course scores on knowledge questions (P = 3.5×10(-6)); this was significantly higher (P = 0.003) than students who did not undergo testing, who showed a non-significant improvement. Undergoing personal genome testing and using personal genotype data in the classroom enhanced students' self-reported and assessed knowledge of genomics, and did not appear to cause significant anxiety. At least for self-selected students, the incorporation of personal genome testing can be an effective educational tool to teach important concepts of clinical genomic testing.

View details for DOI 10.1371/journal.pone.0068853

View details for PubMedID 23935898

Abstract

In 2009, the California Genetic Disease Branch introduced an aneuploidy screening program allowing Medi-Cal (state insured) patients access to state-sponsored first-trimester screening. The objective of this study was to assess the effect of greater access to prenatal screening on available resources at a single center.Data of prenatal screening and diagnostic procedures performed 4 months before the introduction of the program were compared with those of 12 months following the introduction.Between December 2008 and March 2010, 7689 women underwent first trimester screening, 1286 underwent amniocentesis and 398 underwent chorionic villus sampling. When a comparison was made between the 4 months before and the 12 months after the program's introduction, a greater number of nuchal translucency (NT) examinations was seen to have been performed (384 per month vs 513 per month, P=0.001). Prenatal diagnostic procedures did not increase, but a greater proportion was performed for positive screen results.Introduction of the California screening program was associated with increased NT procedures and fewer invasive procedures for advanced maternal age.

View details for DOI 10.1038/jp.2012.8

View details for Web of Science ID 000311831700002

View details for PubMedID 22402484

Abstract

To date, an interstitial deletion of 9p13 has been described only two times in the medical literature. These reports were based on routine chromosomal analysis. We report on two additional patients with an interstitial deletion of 9p13 further defined on array CGH who share clinical features with the other two patients previously described. Our first patient is a 16-year-old girl with a 5.9?Mb deletion at 9p13.3-9p13.1, initially detected on routine karyotype analysis and further characterized on array CGH. Our second patient is a 7½-year-old boy with a 4.8?Mb deletion also at 9p13.3-9p13.1. Patients with 9p13 deletion appear to have mild to moderate developmental delay, social and interactive personality, behavior issues such as attention deficit-hyperactivity disorder, short stature, prominent antihelices, hypoplastic nails, and precocious/early puberty. Our 16-year-old patient is the oldest patient described thus far. This report further characterizes this condition and helps to delineate the long-term prognosis in these patients.

View details for DOI 10.1002/ajmg.a.35536

View details for Web of Science ID 000310068700037

View details for PubMedID 22887577

Abstract

Autosomal dominant conditions are known to be associated with advanced paternal age, and it has been suggested that retinoblastoma (Rb) also exhibits a paternal age effect due to the paternal origin of most new germline RB1 mutations. To further our understanding of the association of parental age and risk of de novo germline RB1 mutations, we evaluated the effect of parental age in a cohort of Rb survivors in the United States. A cohort of 262 Rb patients was retrospectively identified at one institution, and telephone interviews were conducted with parents of 160 survivors (65.3%). We classified Rb survivors into three groups: those with unilateral Rb were classified as sporadic if they had no or unknown family history of Rb, those with bilateral Rb were classified as having a de novo germline mutation if they had no or unknown family history of Rb, and those with unilateral or bilateral Rb, who had a family history of Rb, were classified as familial. We built two sets of nested logistic regression models to detect an increased odds of the de novo germline mutation classification related to older parental age compared to sporadic and familial Rb classifications. The modeling strategy evaluated effects of continuous increasing maternal and paternal age and 5-year age increases adjusted for the age of the other parent. Mean maternal ages for survivors classified as having de novo germline mutations and sporadic Rb were similar (28.3 and 28.5, respectively) as were mean paternal ages (31.9 and 31.2, respectively), and all were significantly higher than the weighted general US population means. In contrast, maternal and paternal ages for familial Rb did not differ significantly from the weighted US general population means. Although we noted no significant differences between mean maternal and paternal ages between each of the three Rb classification groups, we found increased odds of a survivor being in the de novo germline mutation group for each 5-year increase in paternal age, but these findings were not statistically significant (de novo vs. sporadic ORs 30-34 = 1.7 [0.7-4], ? 35 = 1.3 [0.5-3.3]; de novo vs. familial ORs 30-34 = 2.8 [1.0-8.4], ? 35 = 1.6 [0.6-4.6]). Our study suggests a weak paternal age effect for Rb resulting from de novo germline mutations consistent with the paternal origin of most of these mutations.

View details for DOI 10.1007/s00439-011-1126-2

View details for Web of Science ID 000305195400010

View details for PubMedID 22203219

Abstract

Consanguineous unions have been associated with an increased susceptibility to various forms of inherited disease. Although consanguinity is known to contribute to recessive diseases, the potential role of consanguinity in certain common birth defects is less clear, particularly since the disease pathophysiology may involve genetic and environmental/epigenetic factors. In this study, we ask whether consanguinity affects one of the most common birth defects, congenital heart disease, and identify areas for further research into these birth defects, since consanguinity may now impact health on a near-global basis. A systematic review of consanguinity in congenital heart disease was performed, focusing on non-syndromic disease, with the methodologies and results from studies of different ethnic populations compared. The risks for congenital heart disease have been assessed and summarized collectively and by individual lesion. The majority of studies support the view that consanguinity increases the prevalence of congenital heart disease, however, the study designs differed dramatically. Only a few (n = 3) population-based studies that controlled for potential sociodemographic confounding were identified, and data on individual cardiac lesions were limited by case numbers. Overall the results suggest that the risk for congenital heart disease is increased in consanguineous unions in the studied populations, principally at first-cousin level and closer, a factor that should be considered in empiric risk estimates in genetic counseling. However, for more precise risk estimates a better understanding of the underlying disease factors is needed.

View details for DOI 10.1002/ajmg.a.35272

View details for Web of Science ID 000303000200043

View details for PubMedID 22488956

View details for Web of Science ID 000300545400002

View details for PubMedID 22474724

Abstract

Basal cell nevus syndrome (BCNS), also known as Gorlin syndrome (OMIM #109400) is a well-described rare autosomal dominant condition due to haploinsufficiency of PTCH1. With the availability of comparative genomic hybridization arrays, increasing numbers of individuals with microdeletions involving this locus are being identified. We present 10 previously unreported individuals with 9q22.3 deletions that include PTCH1. While 7 of the 10 patients (7 females, 3 males) did not meet strict clinical criteria for BCNS at the time of molecular diagnosis, almost all of the patients were too young to exhibit many of the diagnostic features. A number of the patients exhibited metopic craniosynostosis, severe obstructive hydrocephalus, and macrosomia, which are not typically observed in BCNS. All individuals older than a few months of age also had developmental delays and/or intellectual disability. Only facial features typical of BCNS, except in those with prominent midforeheads secondary to metopic craniosynostosis, were shared among the 10 patients. The deletions in these individuals ranged from 352? kb to 20.5 ?Mb in size, the largest spanning 9q21.33 through 9q31.2. There was significant overlap of the deleted segments among most of the patients. The smallest common regions shared among the deletions were identified in order to localize putative candidate genes that are potentially responsible for each of the non-BCNS features. These were a 929? kb region for metopic craniosynostosis, a 1.08 ?Mb region for obstructive hydrocephalus, and a 1.84? Mb region for macrosomia. Additional studies are needed to further characterize the candidate genes within these regions.

View details for DOI 10.1002/ajmg.a.34216

View details for Web of Science ID 000299331900016

View details for PubMedID 22190277

Abstract

To investigate pregnant women's level of future interest in noninvasive prenatal diagnosis (NIPD) and what factors might affect expected uptake of this testing.Written questionnaires were administered to women in their third trimester.One hundred fourteen women returned the questionnaire (80.9% response rate). Of these, 71.9% reported interest in NIPD, 22.7% were ambivalent, and 5.4% were uninterested. Safety of the fetus was the single most important factor in 75% of women's decisions. Factors associated with increased interest in NIPD included: older age (p?=?0.036), higher education (p?=?0.013), Caucasian or Asian ethnicity (p?=?0.011), and higher likelihood to terminate an affected pregnancy (p?=?0.002). Nearly 20% of women reported that they would do whatever their doctor recommended regarding NIPD, and 94.4% of women wished to meet with a genetic counselor at some point to discuss NIPD.The majority of pregnant women report hypothetical interest in NIPD, primarily because of increased safety for the fetus, although a significant minority are uninterested or ambivalent. Discussions with healthcare providers regarding NIPD, and their recommendations, are likely to be an important factor in women's decisions about this testing. As such, adequate discussion of the implications of prenatal diagnostic testing will be critical.

View details for DOI 10.1002/pd.2888

View details for Web of Science ID 000298566900013

View details for PubMedID 22028097

Abstract

Marfan syndrome (MFS) is a multisystem connective tissue disorder with primary involvement of the ocular, cardiovascular, and skeletal systems. We report on eight patients, all presenting initially with bilateral ectopia lentis (EL) during early childhood. These individuals did not have systemic manifestations of MFS, and did not fulfill the revised Ghent diagnostic criteria. However, all patients had demonstratable, disease-causing missense mutations in the FBN1 gene. Based on molecular results, cardiovascular imaging was recommended and led to the identification of mild aortic root changes in seven of the eight patients. The remaining patient had mitral valve prolapse with a normal appearing thoracic aorta. The findings presented in this paper validate the necessity of FBN1 gene testing in all individuals presenting with isolated EL. As we observed, these individuals are at increased risk of cardiovascular complications. Furthermore, we also noted that the majority of our patient cohort's mutations occurred in the 5' portion of the FBN1 gene, and were found to affect highly conserved cysteine residues, which may indicate a possible genotype-phenotype correlation. We conclude that in patients with isolated features of EL, FBN1 mutation analysis is necessary to aid in providing prompt diagnosis, and to identify patients at risk for potentially life-threatening complications. Additionally, knowledge of the type and location of an FBN1 mutation may be useful in providing further clinical correlation regarding phenotypic progression and appropriate medical management.

View details for DOI 10.1002/ajmg.a.34245

View details for Web of Science ID 000297199700009

View details for PubMedID 21932315

Abstract

Tuberous sclerosis complex (TSC) is an autosomal dominant multisystem disorder characterized by abnormalities involving the skin, brain, kidney (angiomyolipomas, cysts), and heart. Horseshoe kidney has not been considered to be a common renal manifestation of TSC but it has been previously reported in two patients with TSC. We report on two unrelated females with typical manifestations of TSC, horseshoe kidney, and an identical variant c.5138G>A in exon 39 (p.Arg1713His) of TSC2 gene. These cases provide evidence that horseshoe kidney is associated with TSC and add to the evidence for the pathogenicity of this variant. Furthermore, one of the patients also had a diaphragmatic hernia which has been reported twice in the medical literature in individuals with TSC. It is possible that a diaphragmatic hernia is another rare manifestation of TSC and that TSC should be included in the differential diagnosis of infants with a diaphragmatic hernia. Given that both a horseshoe kidney and a diaphragmatic hernia are findings that can be detected prenatally on an ultrasound examination, our findings may have implications for prenatal genetic counseling.

View details for DOI 10.1002/ajmg.a.34197

View details for Web of Science ID 000295326300032

View details for PubMedID 21910228

Abstract

We report on the clinical findings in siblings affected by the recently characterized X-linked form of hereditary cardiac valvular dystrophy or cardiac valve disease (OMIM 314400) due to mutations in the FLNA gene and review the literature on this condition. Although FLNA related cardiac valve disease is presumed to be a rare disorder, it is likely underdiagnosed. Several features of this condition may aid in its identification. FLNA related valvular disease can be recognized on the basis of its distinctive inheritance, early age of onset, and frequent multi-valve involvement.

View details for DOI 10.1002/ajmg.a.34132

View details for Web of Science ID 000294182500031

View details for PubMedID 21815255

Abstract

Medical schools are being approached by direct-to-consumer genotyping companies about genotyping faculty or trainees as a method to "teach" them about the potential implications of genotyping. In thinking about the future incorporation of genotyping into a graduate level genetics course, the purpose of this study was 2-fold: first, to assess knowledge, attitudes, and beliefs of students toward personal genomics as it related to themselves as both as customers and future physicians and as it related to consumers at large, and second, to determine the impact of the course (as taught without genotyping) on knowledge, attitudes, and beliefs.We surveyed first-year medical students and graduate students before and after a core genetics course.After the course, students were less likely to believe that genotyping information would be useful to physicians, patients, or consumers; genotyping would provide information to improve their own personal health; or personal genomic testing services are diagnostic of medical conditions. They were more likely to answer knowledge questions accurately after the course but still had difficulty with clinical interpretation. Despite these changes, a slight majority of students were, and remained, interested in undergoing genotyping themselves. Of note, the number who believed genotyping "would help them understand genetic concepts better than someone else's data" decreased. General curiosity was the most commonly chosen reason for interest in undergoing genotyping, and approximately 50% of respondents expressed concern about confidentiality of results.In conclusion, even without the genotyping process, an educational program about genotyping increased knowledge, particularly about the clinical limitations of genotyping, but student interest in genotyping did not significantly change. Institutions thinking about offering genotyping to their students as part of a learning experience should consider the pros and cons of doing so.

View details for DOI 10.1097/GIM.0b013e31820562f6

View details for Web of Science ID 000290435700005

View details for PubMedID 21270640

Abstract

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder with a high carrier frequency in the general population. The severity of this disorder indicates the importance of early prenatal detection. In medical literature, there are a few published case reports of enlarged nuchal translucency (NT) measurement in association with a diagnosis of SMA in the fetus. Our goal is to determine whether SMA in infants is associated with a history of an increased NT measurement during pregnancy.Using contact information obtained through SMA family support groups, women who had recently given birth to infants affected with SMA were identified and queried about NT ultrasound results during the pregnancy. NT values were confirmed via ultrasound report to determine whether SMA was associated with a history of an enlarged NT measurement.Twelve SMA affected infants with confirmed NT results during the pregnancy were identified. All fetuses had normal NT values ranging from 0.7 to 2.4 mm.In this series, SMA did not appear to be associated with an enlarged NT.

View details for DOI 10.1002/pd.2646

View details for Web of Science ID 000288620000002

View details for PubMedID 21287566

Abstract

Carpenter syndrome, a rare autosomal recessive disorder characterized by a combination of craniosynostosis, polysyndactyly, obesity, and other congenital malformations, is caused by mutations in RAB23, encoding a member of the Rab-family of small GTPases. In 15 out of 16 families previously reported, the disease was caused by homozygosity for truncating mutations, and currently only a single missense mutation has been identified in a compound heterozygote. Here, we describe a further 8 independent families comprising 10 affected individuals with Carpenter syndrome, who were positive for mutations in RAB23. We report the first homozygous missense mutation and in-frame deletion, highlighting key residues for RAB23 function, as well as the first splice-site mutation. Multi-suture craniosynostosis and polysyndactyly have been present in all patients described to date, and abnormal external genitalia have been universal in boys. High birth weight was not evident in the current group of patients, but further evidence for laterality defects is reported. No genotype-phenotype correlations are apparent. We provide experimental evidence that transcripts encoding truncating mutations are subject to nonsense-mediated decay, and that this plays an important role in the pathogenesis of many RAB23 mutations. These observations refine the phenotypic spectrum of Carpenter syndrome and offer new insights into molecular pathogenesis.

View details for DOI 10.1002/humu.21457

View details for Web of Science ID 000288464100002

View details for PubMedID 21412941

Abstract

Prenatal genetic screening and diagnostic testing can identify many disorders that will require specialized newborn care and follow-up. Pediatricians should be aware of recent advances in testing that may have implications for their patients and families.Over the last half decade, there have been important changes in the breadth and depth of prenatal screening and diagnostic procedures. Carrier screening for selected genetic disorders is now offered routinely to pregnant women or those contemplating pregnancy. Newly developed strategies for first-trimester screening for fetal chromosome abnormalities have improved the detection rate for these disorders, while maintaining a low screen-positive rate. The American College of Obstetricians and Gynecologists and the American College of Medical Genetics now recommend that invasive prenatal diagnostic testing be made available to all pregnant women, regardless of age or prenatal screening results. And prenatal ultrasound findings of unknown clinical significance require that pediatricians provide appropriate follow-up in the newborn period and beyond.Prenatal genetic screening and diagnostic tests are changing rapidly, and results of these tests may impact the postnatal evaluation and treatment strategies for pediatric care.

View details for DOI 10.1097/MOP.0b013e32833f5f6e

View details for Web of Science ID 000284143600021

View details for PubMedID 20829690

Abstract

DNA copy-number variations (CNVs) underlie many neuropsychiatric conditions, but they have been less studied in cancer. We report the association of a 17p13.1 CNV, childhood-onset developmental delay (DD), and cancer. Through a screen of over 4000 patients with diverse diagnoses, we identified eight probands harboring microdeletions at TP53 (17p13.1). We used a purpose-built high-resolution array with 93.75% breakpoint accuracy to fine map these microdeletions. Four patients were found to have a common phenotype including DD, hypotonia, and hand and foot abnormalities, constituting a unique syndrome. Notably, these patients were not affected with cancer. Moreover, none of the TP53-deletion patients affected with cancer (n = 4) had neurocognitive impairments. DD patients have larger deletions, which encompass but do not disrupt TP53, whereas cancer-affected patients harbor CNVs with at least one breakpoint within TP53. Most 17p13.1 deletions arise by Alu-mediated nonallelic homologous recombination. Furthermore, we identify a critical genomic region associated with DD and containing six underexpressed genes. We conclude that, although they overlap, 17p13.1 CNVs are associated with distinct phenotypes depending on the position of the breakpoint with respect to TP53. Further, detailed characterization of breakpoints revealed a common formation signature. Future studies should consider whether other loci in the genome also give rise to phenotypically distinct disorders by means of a common mechanism, resulting in a similar formation signature.

View details for DOI 10.1016/j.ajhg.2010.10.007

View details for Web of Science ID 000284668400008

View details for PubMedID 21056402

Abstract

Laboratory evaluation of patients with developmental delay/intellectual disability, congenital anomalies, and dysmorphic features has changed significantly in the last several years with the introduction of microarray technologies. Using these techniques, a patient's genome can be examined for gains or losses of genetic material too small to be detected by standard G-banded chromosome studies. This increased resolution of microarray technology over conventional cytogenetic analysis allows for identification of chromosomal imbalances with greater precision, accuracy, and technical sensitivity. A variety of array-based platforms are now available for use in clinical practice, and utilization strategies are evolving. Thus, a review of the utility and limitations of these techniques and recommendations regarding present and future application in the clinical setting are presented in this study.

View details for DOI 10.1097/GIM.0b013e3181f8baad

View details for Web of Science ID 000284105800012

View details for PubMedID 20962661

Abstract

Kallmann syndrome (KS) is defined by the association of idiopathic hypogonadotropic hypogonadism and anosmia/hyposmia. Diagnosis is frequently delayed, however, because hypogonadotropic hypogonadism is usually not apparent until puberty and individuals with anosmia/hyposmia are often unaware of this sensory deficit. Mutations in at least six genes have been associated with KS; however, the sensitivity of molecular testing is only about 30% and, therefore, the diagnosis is largely based on clinical findings. We describe the findings in six individuals with KS, which demonstrate the utility of associated anomalies in making this diagnosis. Analysis of our case series and literature review suggests the consideration of KS for males with microphallus and/or cryptorchidism and for any patient with hearing loss, renal agenesis, and/or synkinesis. Conversely, patients with features of KS should have an audiology evaluation and a renal ultrasound.

View details for DOI 10.1002/ajmg.a.33442

View details for Web of Science ID 000284005700019

View details for PubMedID 20949504

Abstract

Caudal appendage is a rare but reported finding seen in association with craniosynostosis. We report a newborn with caudal appendage secondary to sacrococcygeal eversion, a cloverleaf skull, choanal atresia, and a heterozygous mutation of Y375C in the juxtamembrane domain (exon 11) of fibroblast growth factor receptor 2 (FGFR2). Further support of this association are 22 other cases of craniosynostosis with caudal appendage or sacrococcygeal eversion in the literature. Of these, 19 had detectable mutations in FGFR2; 5, the same mutation; and 5, a similar substitution of cysteine for serine. We hypothesize that the association of craniosynostosis and caudal appendage is due to abnormal expression of FGFR2 in the tail bud of a developing embryo based on animal models. Our case and those reported in the literature suggest that in patients with caudal appendage and craniosynostosis, FGRF2 analysis should include regions outside the commonly tested exons 8 and 10, particularly the juxtamembrane domain.

View details for DOI 10.1097/SCS.0b013e3181ef2bab

View details for Web of Science ID 000282003300009

View details for PubMedID 20856019

Abstract

Noninvasive prenatal diagnosis with cell-free DNA in maternal plasma is challenging because only a small portion of the DNA sample is derived from the fetus. A few previous studies provided size-range estimates of maternal and fetal DNA, but direct measurement of the size distributions is difficult because of the small quantity of cell-free DNA.We used high-throughput paired-end sequencing to directly measure the size distributions of maternal and fetal DNA in cell-free maternal plasma collected from 3 typical diploid and 4 aneuploid male pregnancies. As a control, restriction fragments of lambda DNA were also sequenced.Cell-free DNA had a dominant peak at approximately 162 bp and a minor peak at approximately 340 bp. Chromosome Y sequences were rarely longer than 250 bp but were present in sizes of <150 bp at a larger proportion compared with the rest of the sequences. Selective analysis of the shortest fragments generally increased the fetal DNA fraction but did not necessarily increase the sensitivity of aneuploidy detection, owing to the reduction in the number of DNA molecules being counted. Restriction fragments of lambda DNA with sizes between 60 bp and 120 bp were preferentially sequenced, indicating that the shotgun sequencing work flow introduced a bias toward shorter fragments.Our results confirm that fetal DNA is shorter than maternal DNA. The enrichment of fetal DNA by size selection, however, may not provide a dramatic increase in sensitivity for assays that rely on length measurement in situ because of a trade-off between the fetal DNA fraction and the number of molecules being counted.

View details for DOI 10.1373/clinchem.2010.144188

View details for Web of Science ID 000280501400016

View details for PubMedID 20558635

View details for DOI 10.1016/S0140-6736(10)60599-5

View details for Web of Science ID 000277890200036

View details for PubMedID 20434765

Abstract

The cost of genomic information has fallen steeply, but the clinical translation of genetic risk estimates remains unclear. We aimed to undertake an integrated analysis of a complete human genome in a clinical context.We assessed a patient with a family history of vascular disease and early sudden death. Clinical assessment included analysis of this patient's full genome sequence, risk prediction for coronary artery disease, screening for causes of sudden cardiac death, and genetic counselling. Genetic analysis included the development of novel methods for the integration of whole genome and clinical risk. Disease and risk analysis focused on prediction of genetic risk of variants associated with mendelian disease, recognised drug responses, and pathogenicity for novel variants. We queried disease-specific mutation databases and pharmacogenomics databases to identify genes and mutations with known associations with disease and drug response. We estimated post-test probabilities of disease by applying likelihood ratios derived from integration of multiple common variants to age-appropriate and sex-appropriate pre-test probabilities. We also accounted for gene-environment interactions and conditionally dependent risks.Analysis of 2.6 million single nucleotide polymorphisms and 752 copy number variations showed increased genetic risk for myocardial infarction, type 2 diabetes, and some cancers. We discovered rare variants in three genes that are clinically associated with sudden cardiac death-TMEM43, DSP, and MYBPC3. A variant in LPA was consistent with a family history of coronary artery disease. The patient had a heterozygous null mutation in CYP2C19 suggesting probable clopidogrel resistance, several variants associated with a positive response to lipid-lowering therapy, and variants in CYP4F2 and VKORC1 that suggest he might have a low initial dosing requirement for warfarin. Many variants of uncertain importance were reported.Although challenges remain, our results suggest that whole-genome sequencing can yield useful and clinically relevant information for individual patients.National Institute of General Medical Sciences; National Heart, Lung And Blood Institute; National Human Genome Research Institute; Howard Hughes Medical Institute; National Library of Medicine, Lucile Packard Foundation for Children's Health; Hewlett Packard Foundation; Breetwor Family Foundation.

View details for Web of Science ID 000277655100025

View details for PubMedID 20435227

View details for DOI 10.1002/ajmg.a.33006

View details for Web of Science ID 000270745000043

View details for PubMedID 19764021

Abstract

Mutations in the gene Indian Hedgehog (IHH) that cause Brachydactyly A-1 (BDA1) have been restricted to a specific region of the N-terminal active fragment of Indian Hedgehog involving codons 95, 100, 131, and 154. We describe two novel mutations in codons 128 and 130, not previously implicated in BDA1. Furthermore, we identified an independent mutation at codon 131 and we also describe a New Zealand family, which carries the 'Farabee' founder mutation and haplotype. All of the BDA1 mutations occur in a restricted area of the N-terminal active fragment of the IHH and are in contrast to those mutations causing an autosomal recessive acrocapitofemoral dysplasia, whose mutations are located at the distal N- and C-terminal regions of IHH-N and are physically separated from the BDA1-causing mutations. The identification of multiple independent mutations in codons 95, 100, and now in 131, implicate a discrete function for this region of the protein. Finally, we present a clinical review of all reported and confirmed cases of BDA1, highlighting features of the disorder, which add to the spectrum of the IHH mutations.

View details for DOI 10.1038/ejhg.2009.18

View details for Web of Science ID 000269449900004

View details for PubMedID 19277064

Abstract

Dandy-Walker malformation (DWM), the most common human cerebellar malformation, has only one characterized associated locus. Here we characterize a second DWM-linked locus on 6p25.3, showing that deletions or duplications encompassing FOXC1 are associated with cerebellar and posterior fossa malformations including cerebellar vermis hypoplasia (CVH), mega-cisterna magna (MCM) and DWM. Foxc1-null mice have embryonic abnormalities of the rhombic lip due to loss of mesenchyme-secreted signaling molecules with subsequent loss of Atoh1 expression in vermis. Foxc1 homozygous hypomorphs have CVH with medial fusion and foliation defects. Human FOXC1 heterozygous mutations are known to affect eye development, causing a spectrum of glaucoma-associated anomalies (Axenfeld-Rieger syndrome, ARS; MIM no. 601631). We report the first brain imaging data from humans with FOXC1 mutations and show that these individuals also have CVH. We conclude that alteration of FOXC1 function alone causes CVH and contributes to MCM and DWM. Our results highlight a previously unrecognized role for mesenchyme-neuroepithelium interactions in the mid-hindbrain during early embryogenesis.

View details for DOI 10.1038/ng.422

View details for Web of Science ID 000269382100019

View details for PubMedID 19668217

Abstract

Diabetes is the most common endocrinologic complication during pregnancy, and poor control can lead to a variety of congenital anomalies in the fetus. However, it is often difficult to differentiate between diabetes-related anomalies and an underlying genetic syndrome. In the 1990s it was proposed that preaxial hallucal polydactyly, particularly when proximally placed, was a distinguishing feature of diabetic embryopathy.We summarize the clinical findings in 18 patients (five previously reported in abstract form) with diabetic embryopathy and preaxial hallucal polydactyly to determine which features are most suggestive of diabetic embryopathy.All 18 patients had preaxial hallucal polydactyly (seven bilateral, 11 unilateral), of which 15 patients had proximal implantation of the extra hallux. Further skeletal findings included the following: segmentation anomalies of the spine, equinovarus deformity of the feet, tibial hemimelia, hip dysplasia, and femoral hypoplasia. Upper limb malformations were rare. Eleven of the 18 mothers had prepregnancy insulin-dependent diabetes, while one mother had prepregnancy type 2 diabetes that required insulin therapy in the 3(rd) trimester. Five mothers had gestational diabetes that required insulin and one mother had gestational diabetes that was controlled by diet. The majority of mothers had poorly controlled diabetes during the pregnancy.Proximally placed preaxial hallucal polydactyly, particularly when coupled with segmentation anomalies of the spine and tibial hemimelia, is highly suggestive of diabetic embryopathy. Varying degrees of diabetes in the mothers point to a possible genetic predisposition interacting with the teratogenic effects of poor glycemic control leading to specific limb anomalies.

View details for DOI 10.1002/bdra.20503

View details for Web of Science ID 000262904800003

View details for PubMedID 18798547

Abstract

Microarray-based comparative genomic hybridization can determine genome-wide copy number alterations at the kilobase level. We highlight the clinical utility of microarray-based comparative genomic hybridization in determining tumor susceptibility in 3 patients with dysmorphic features and developmental delay, likely decreasing both morbidity and mortality in these patients.

View details for DOI 10.1016/j.jpeds.2008.07.045

View details for Web of Science ID 000262272500031

View details for PubMedID 19187739

Abstract

We directly sequenced cell-free DNA with high-throughput shotgun sequencing technology from plasma of pregnant women, obtaining, on average, 5 million sequence tags per patient sample. This enabled us to measure the over- and underrepresentation of chromosomes from an aneuploid fetus. The sequencing approach is polymorphism-independent and therefore universally applicable for the noninvasive detection of fetal aneuploidy. Using this method, we successfully identified all nine cases of trisomy 21 (Down syndrome), two cases of trisomy 18 (Edward syndrome), and one case of trisomy 13 (Patau syndrome) in a cohort of 18 normal and aneuploid pregnancies; trisomy was detected at gestational ages as early as the 14th week. Direct sequencing also allowed us to study the characteristics of cell-free plasma DNA, and we found evidence that this DNA is enriched for sequences from nucleosomes.

View details for DOI 10.1073/pnas.0808319105

View details for Web of Science ID 000260597400037

View details for PubMedID 18838674

Abstract

Deletion 1p36 syndrome is a recently delineated disorder, considered to be the most common subtelomeric microdeletion syndrome (1 in 5000 newborns). 1p36.3 deletions account for 0.5% to 1.2% of idiopathic mental retardation; thus, knowledge about the condition is important for pediatricians caring for such patients. Despite 100 reported cases, little is known about its natural history. Our aim was to delineate the natural history of deletion 1p36 and develop complete and accurate information with which to answer families' questions in the clinical setting.We evaluated 60 patients with the 1p36 deletion syndrome (41 female, 19 male). All underwent physical and neurologic assessments, and most received a psychological evaluation. Standard cytogenetics, fluorescence in situ hybridization of the subtelomeric regions, or array comparative genomic hybridization were used for diagnosis.Fourteen cases were detected by standard cytogenetics, and 46 were detected by fluorescence in situ hybridization of the subtelomeric regions or array comparative genomic hybridization. Occipitofrontal circumference was at < or = 2nd centile in 95%, and height and weight ranged between the < 3rd and 90th centiles. All patients had straight eyebrows, deep-set eyes, midface hypoplasia, broad nasal root/bridge, long philtrum, and pointed chin. Other features included microbrachycephaly (65%), epicanthus (50%), large, late-closing anterior fontanel (77%), and posteriorly rotated, low-set, abnormal ears (40%). Brachy/camptodactyly and short feet were prominent. Seventy-one percent exhibited heart defects, including 23% with a "noncompaction cardiomyopathy." Fifty-two percent had eye/visual abnormalities, and 64% had visual inattentiveness. Twenty-eight percent had sensorineural deafness, 41% had skeletal anomalies, 25% had abnormal genitalia, and 22% had renal abnormalities. Eighty-eight percent had central nervous system anomalies, and 44% had seizures. All patients demonstrated developmental delay with poor/absent speech; 95% had hypotonia. Twenty-six percent were able to walk alone, and 47% had a behavior disorder. Constant developmental progress was observed in all cases over time. Noncompaction cardiomyopathy and most seizures were controlled by pharmacotherapy.These 60 patients with deletion 1p36 represent the largest clinical series to date and provide new information on several aspects of this disorder, which is characterized by neurodevelopmental disability and a recognizable pattern of malformation.

View details for DOI 10.1542/peds.2007-0929

View details for Web of Science ID 000252877600021

View details for PubMedID 18245432

Abstract

Mental retardation affects approximately 3% of the population, and the background birth defect rate is 3% to 4%. An underlying cause is identified less than 50% of the time. In the cases in which a cause is determined, a chromosomal anomaly is the cause in up to 40%. Laboratory evaluation routinely includes high-resolution karyotyping, subtelomeric fluorescence in situ hybridization analysis, and targeted fluorescence in situ hybridization analysis depending on the clinical features. There are technical limitations to these techniques, however. For example, anomalies less than 2 to 3 Mb in size are undetectable by karyotype, and subtelomeric fluorescence in situ hybridization analysis is a labor-intensive analysis with a relatively low yield. With completion of the Human Genome Project, diagnostic testing is moving toward the use of DNA-based techniques such as comparative genomic hybridization microarray analysis or array comparative genomic hybridization. Although this technology has been used in the evaluation of tumors and cancer patients in the past, it is now being applied in the assessment of patients demonstrating idiopathic mental retardation or developmental delay, dysmorphic features, congenital anomalies, and spontaneous abortions. As with other well-developed cytogenetic studies, there are technical limitations to array comparative genomic hybridization that must be acknowledged and addressed before its widespread use. A variety of array-based technologies are now available on a clinical basis. We discuss the utility and limitations of using this technology in the evaluation of individuals with mental retardation and malformations, citing the existing literature.

View details for DOI 10.1097/GIM.0b013e31814cec3a

View details for Web of Science ID 000249640800013

View details for PubMedID 17873654

Abstract

Mowat-Wilson syndrome (MWS) is a relatively newly described multiple congenital anomaly/mental retardation syndrome. Haploinsufficiency of a gene termed ZFHX1B (also known as SIP1) on chromosome 2 is responsible for this condition, and clinical genetic testing for MWS recently became available. The majority of reports in the literature originate from Northern Europe and Australia. Here we report our clinical experience with 12 patients diagnosed with MWS within a 2-year period of time in the United States, with particular emphasis on clinical characteristics and management strategies. Individuals with this condition have characteristic facial features, including microcephaly, hypertelorism, medially flared and broad eyebrows, prominent columella, pointed chin, and uplifted earlobes, which typically prompt the clinician to consider the diagnosis. Medical issues in our cohort of patients included seizures (75%) with no predeliction for any particular seizure type; agenesis of the corpus callosum (60% of our patients studied); congenital heart defects (75%), particularly involving the pulmonary arteries and/or valves; hypospadias (55% of males); severely impaired or absent speech (100% of individuals over 1 year of age) with relatively spared receptive language; and Hirschsprung disease (50%) or chronic constipation (25%). The incidence of MWS is unknown, but based on the number of patients identified in a short period of time within the US, it is likely greatly under recognized. MWS should be considered in any individual with severely impaired or absent speech, especially in the presence of seizures and anomalies involving the pulmonary arteries (particularly pulmonary artery sling) or pulmonary valves.

View details for DOI 10.1002/ajmg.a.31530

View details for Web of Science ID 000242466200005

Abstract

Genitopatellar syndrome is a newly described disorder characterized by absent/hypoplastic patellae, lower extremity contractures, urogenital anomalies, dysmorphic features, skeletal anomalies, and agenesis of the corpus callosum. More recently, cardiac anomalies and ectodermal dysplasia have been suggested as additional features of this syndrome. We report on two additional patients with genitopatellar syndrome and expand the spectrum of anomalies to include radio-ulnar synostosis. Since there exists significant overlap in the skeletal phenotype between genitopatellar syndrome and both the nail-patella and short patella syndromes, mutation screening of their causative genes, LMX1B and TBX4, was performed. Although there still does not appear to be an identifiable molecular etiology in genitopatellar syndrome, mutations in these two candidate genes have been excluded in our patients. Since both LMX1B and TBX4 are involved in a common molecular pathway, it is likely that the causative gene of genitopatellar syndrome functions within the same developmental process.

View details for DOI 10.1002/ajmg.a.31258

View details for Web of Science ID 000238799900011

Abstract

Kabuki syndrome (KS) comprises multiple congenital anomalies and distinctive facial appearance. Although a number of chromosome abnormalities have been described in patients with KS-like phenotypes, no consensus has been reached regarding the genetic basis underlying the classic Kabuki phenotype. A recent study reported on 8p22-8p23.1 duplication in patients diagnosed with KS; however, a number of other studies have not found this duplication in patients with classic KS. We report on a girl with triplication of 8p22-8p23 who has mental retardation and some features suggestive of KS, including growth retardation, left-sided obstructive heart lesion, long-appearing palpebral fissures, hypertelorism, sparse lateral eyebrows, prominent ears, and persistent fetal fingertip pads. She does not have the typical facial gestalt of KS, nor does she have other more specific findings of KS. We propose that abnormal copy number of genes in the 8p22-8p23 region results in a syndrome of multiple congenital anomalies with many features that overlap with classic KS. However, data from this patient and others with similar duplications in the literature suggest that duplication or triplication of 8p22-8p23 represents a recognizable pattern of malformation distinct from classic KS. The exact genetic abnormality underlying KS currently remains unknown.

View details for DOI 10.1002/ajmg.a.31036

View details for Web of Science ID 000234491600012

Abstract

A genetics evaluation of children with pervasive developmental disorders (PDDs) identifies a diagnosis in 6% to 15% of cases. However, previous studies have not measured the incidence of genetic disorders among children with autistic-like features who do not necessarily meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria for PDD.We identified 101 patients at our institution referred for PDD, autism, Asperger syndrome, or autistic features. Seventy-eight were males and 23 were females, giving a male-to-female ratio of 3.4:1. No diagnosis was identified on examination alone, although Rett syndrome was suspected in six females. Seventeen patients did not undergo any type of testing because of noncompliance.Of the remaining 84 patients analyzed, seven (8.3%) were found to have abnormalities on testing. Three chromosomal anomalies were found: one with 5p duplication, one with low-level mosaicism for trisomy 21, and one with an unbalanced 10;22 translocation. Three females were diagnosed with Rett syndrome after MECP2 analysis identified a disease-causing mutation. The remaining patient was found to have an elevated urine orotic acid, with a normal ammonia level, of unknown significance.On the basis of our series, the yield of a genetics evaluation in patients with features of PDD who do not necessarily meet the Diagnostic and Statistical Manual for Mental Disorders, Fourth Edition criteria is 8.3%. Approximately half of these were the result of a chromosomal abnormality. Three cases of Rett syndrome were identified for which autistic behaviors are a well-described feature. These findings suggest that a high-resolution karyotype provides the greatest diagnostic yield for patients with autistic-like features. MECP2 analysis should be considered for females who present with autistic behaviors.

View details for DOI 10.1097/01.gim.0000195304.45116.96

View details for Web of Science ID 000234850900007

View details for PubMedID 16418599

Abstract

With improved cytogenetic techniques, small deletions and duplications are being identified with increased frequency. We report four cases with terminal deletions involving the 6p24- and 6p25-pter chromosomal segment who exhibit a distinct, recognizable pattern of malformations including hypertelorism, downslanting palpebral fissures, flat nasal bridge, Dandy-Walker malformation/variant, congenital heart defects, anterior eye-chamber abnormalities, hearing loss, and developmental delay. We also compare the clinical aspects of these patients to those of previously reported cases in the literature with similar terminal deletions of chromosome 6p. Routine chromosome analysis can miss this deletion, therefore, high-resolution chromosome analysis is indicated for individuals who exhibit these distinct features. Furthermore, individuals with this deletion should have an ophthalmologic exam, cardiac evaluation, head imaging, renal ultrasound, and formal hearing evaluation.

View details for DOI 10.1002/ajmg.a.30784

View details for Web of Science ID 000230229100009

Abstract

The purpose of this study was to determine factors that influence the detection rate of sonographic markers of fetal aneuploidy (SMFA).We reviewed the sonographic images of 160 consecutive second-trimester trisomic fetuses for the presence of SMFA, either structural anomalies or sonographic soft markers.One hundred forty-nine (93.1%) records were complete and analyzed; 78 cases (52.3%) were identified with 1 or more SMFA. Sonographic markers of fetal aneuploidy were detected in 42.7%, 75.0%, and 90.9% of trisomies 21, 18, and 13, respectively (P<.005). The detection rate of SMFA had a positive linear correlation with gestational age (adjusted R(2)=0.64; P<.002). Sonographic markers of fetal aneuploidy were detected in 43.7% of fetuses of less than 18.0 weeks' gestation and 64.5% of fetuses of 18.0 weeks' gestation or greater (likelihood ratio=6.4; P<.01). Sonographic markers of fetal aneuploidy were detected in 23.5% of patients with suboptimal image quality versus 58.3% of the others (likelihood ratio=7.5; P<.05). The rate of structural malformation was similar between the male and female fetuses, whereas that of soft markers was 49.4% in male and 30.0% in female fetuses (odds ratio=2.3; range, 1.2-4.5; P<.02). Factor analysis showed that some soft markers and some structural anomalies tended to appear together.The type of fetal trisomy, gestational age, sex, and quality of images influence the detection rate of SMFA. The highest detection rate for SMFA in the second trimester is at or above 18 weeks' gestational age. Certain markers are detected in clusters. These findings may explain, in part, the variability in reported rates of detection of SMFA among trisomic fetuses. These findings need to be prospectively tested in the general population of pregnancies for applicability to sonographic risk calculations for fetal trisomies.

View details for Web of Science ID 000229461900009

View details for PubMedID 15914685

Abstract

The oculo-auriculo-vertebral (OAV) spectrum is an etiologically heterogeneous condition classically consisting of microtia, hemifacial microsomia, epibulbar dermoids, and vertebral anomalies. Other eye findings described in OAV include upper eyelid colobomas, ptosis, and varying degrees of microphthalmia or even anophthalmia. Iris and/or retinal colobomas have rarely been reported. We describe two familial cases of apparent OAV with ocular colobomas. We postulate that iris and/or retinal colobomas associated with OAV may represent a subgroup within the OAV spectrum with autosomal dominant inheritance, as in the families described herein. Since microtia can result from aberrant migration of neural crest cells into the first and second branchial arches during early embryonic development, and concomitant deficient neural crest migration into the developing eye can lead to ocular coloboma and or iris heterochromia, it may be that the altered gene or genes in our familial cases are involved with regulation of neural crest development.

View details for DOI 10.1002/ajmg.a.30638

View details for Web of Science ID 000228758400003

View details for DOI 10.1002/ajmg.a.30644

View details for Web of Science ID 000228083600020

View details for PubMedID 15759263

Abstract

Mowat-Wilson Syndrome is a recently delineated mental retardation syndrome usually associated with multiple malformations and a recognizable facial phenotype caused by defects of the transcriptional repressor ZFHX1B. To address the question of clinical and mutational variability, we analysed a large number of patients with suspected Mowat-Wilson Syndrome (MWS). Without prior knowledge of their mutational status, 70 patients were classified into "typical MWS", "ambiguous" and "atypical" groups according to their facial phenotype. Using FISH, qPCR and sequencing, ZFHX1B deletions, splice site or truncating mutations were detected in all 28 patients classified as typical MWS. No ZFHX1B defect was apparent in the remaining 15 cases with ambiguous facial features or in the 27 atypical patients. Genotype-phenotype analysis confirmed that ZFHX1B deletions and stop mutations result in a recognizable facial dysmorphism with associated severe mental retardation and variable malformations such as Hirschsprung disease and congenital heart defects. Our findings indicate that structural eye anomalies such as microphthalmia should be considered as part of the MWS spectrum. We also show that agenesis of the corpus callosum and urogenital anomalies (especially hypospadias) are significant positive predictors of a ZFHX1B defect. Based on our observation of affected siblings and the number of MWS cases previously reported, we suggest a recurrence risk of around 1%. The lack of missense mutations in MWS and MWS-like patients suggests there may be other, as yet unrecognized phenotypes, associated with missense mutations of this transcription factor.

View details for DOI 10.1016/j.ejmg.2005.01.003

View details for Web of Science ID 000230162200003

View details for PubMedID 16053902

Abstract

Kabuki syndrome (KS) (Kabuki make-up syndrome, Niikawa-Kuroki syndrome) is a multiple malformation/mental retardation syndrome that was described initially in Japan but is now known to occur in many other ethnic groups. It is characterized by distinctive facial features (eversion of the lower lateral eyelid, arched eyebrows with the lateral one-third dispersed or sparse, depressed nasal tip, and prominent ears), skeletal anomalies, dermatoglyphic abnormalities, short stature, and mental retardation. A number of other manifestations involving other organ systems can aid in the diagnosis and management of KS. This review will focus on the diagnostic criteria, the common and rare features of KS by organ system, and the possible etiology of this interesting condition.

View details for DOI 10.1111/j.1399-0004.2004.00348.x

View details for Web of Science ID 000226772800002

View details for PubMedID 15691356

Abstract

Lateral meningoceles were first described by Lehman et al. [(1977); J Pediatr 90: 49-54] in a patient with other skeletal findings and distinctive craniofacial features. Subsequently, six more patients with the so-called lateral meningocele syndrome (LMS) have been reported. We describe the findings in three new cases and expand the phenotype. The existence of an affected mother and daughter supports the hypothesis that LMS is a dominant disorder affecting primarily the connective tissue.

View details for DOI 10.1002/ajmg.a.30526

View details for Web of Science ID 000227194100001

View details for PubMedID 15666314

Abstract

Over the last 20 years, a wide spectrum of congenital anomalies have been described in association with Kabuki syndrome (KS). However, very little information is available on developmental outcome. As more individuals with this syndrome are recognized and reported, it appears that as many as one-sixth may have normal intelligence. The purpose of this report is to describe the developmental outcome in 15 patients with KS, to determine whether a recognizable pattern of disabilities exist, and whether developmental outcome correlates with the presence of malformations. We ascertained 15 patients with KS from three dysmorphology and clinical genetics services in which developmental milestones and formal developmental testing were available. Based on these patients and a review of the literature, in the absence of major structural brain anomalies, the average intelligence quotient (IQ) in patients with this condition fall within the mild mental retardation range, however, specific developmental outcomes are widely variable, ranging from severe MR to normal intelligence. The presence or absence of hearing loss or major malformations, other than those involving the brain, was not predictive of developmental outcome.

View details for DOI 10.1002/ajmg.a.30338

View details for Web of Science ID 000226181500007

View details for PubMedID 15523636

Abstract

The Kabuki syndrome is a well-established pattern of human malformation with readily recognizable features, however the diagnosis is rarely made in the newborn period. The purpose of this study was to determine if there exists a neonatal phenotype for this disorder. We ascertained 16 infants evaluated in the first 28 days of life by a dysmorphologist who subsequently received the diagnosis of Kabuki syndrome. The average age of initial evaluation was 8 days and the average age of diagnosis was 2 years 6 months. Based on these findings, it is suggested that the distinctive clinical phenotype seen in older patients is also evident in the newborn period.

View details for DOI 10.1002/ajmg.a.30336

View details for Web of Science ID 000226181500003

View details for PubMedID 15690369

Abstract

Cryptic subtelomeric chromosome rearrangements account for 6% to 10% of idiopathic mental retardation. As cytogenetic and molecular techniques have become more sophisticated, the number of genetic syndromes attributed to these microdeletions has increased. To date, 64 patients have been described in the literature with a more recently recognized microdeletion syndrome, del 22q13.3. The purpose of this study is to present 11 new cases of this recently described syndrome to delineate further the phenotype and to alert the clinician to another genetic condition that should be considered in the differential diagnosis of early hypotonia, delayed speech acquisition, and autistic behavior.Eleven patients were evaluated in 3 academic institutions. Clinical features and results of cytogenetic testing were recorded and tabulated. Reasons for referral for genetic evaluation included developmental delay, severe expressive speech and language delay, and dysmorphic features.Age of presentation ranged from 5 months to 46 years. There were 10 female patients and 1 male patient. All of the patients exhibited delayed motor development, some degree of hypotonia, and severe expressive speech and language delay. Dysmorphic facial features included epicanthal folds, large cupped ears, underdeveloped philtrum, loss of cupid's bow, and full supraorbital ridges. Six patients exhibited autistic-like behaviors. Microscopically visible chromosome deletions were observed in 6 patients. In the remainder, the deletion was detected with the use of fluorescence in situ hybridization.Hypotonia and developmental delay are nonspecific findings observed in many malformation and genetic syndromes. However, in association with severe speech and language delay and autistic-like behavior, this phenotype may be a significant indication to consider the 22q13 deletion syndrome as a potential cause.

View details for Web of Science ID 000223040000017

View details for PubMedID 15286229

Abstract

To increase awareness of congenital disorders of glycosylation (CDG), we report the features of patients with a variety of clinical presentations ranging from mild hypotonia and strabismus to severe neurologic impairment.Nine North American patients with CDG type I and different ethnic origins were studied.All patients had transferrin isoelectric focusing studies with a type 1 sialotransferrin pattern. Molecular analysis showed the previously described R141H, V231M, and T237M PMM2 mutations in four patients as well as 3 rare mutations (DeltaC389, L104V, and IVS1 -1 G-->A) in the PMM2 gene in two Asian patients.The clinical features of these patients with diverse ethnic backgrounds confirm the variable course of CDG type I. Screening for CDG should be considered in children with relatively mild neurologic impairment, especially if they have suggestive findings such as cerebellar hypoplasia and abnormal fat distribution.

View details for DOI 10.1067/mpd.2002.128658

View details for Web of Science ID 000179182300025

View details for PubMedID 12410200

Abstract

Despite a 21% reduction in the birth rate for adolescents aged 15-19 years between 1991 and 2000, there are still over 470,000 births to adolescents nationwide. The primary purpose of prenatal screening is to determine the risk of a disease or condition affecting either the patient or her fetus. A determination of risk is possible only after an accurate assessment of all information unique to each pregnancy. This assessment includes a medical, obstetrical, social, and family history. Ethnicity-based screening tests should be offered to patients at risk for specific disorders unique to their ancestry, whereas population-based screening tests, such as maternal serum screening and ultrasound screening, should be offered to all pregnant women. Invasive diagnostic testing should be reserved for patients whose pregnancy has been determined to be at risk for a particular disease or condition.

View details for PubMedID 11986037

Abstract

Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant vascular dysplasia. Most cases are caused by mutations in the endoglin gene on chromosome 9 (HHT type 1) or the activin receptor-like kinase 1 gene on chromosome 12 (HHT type 2), which leads to telangiectases and arteriovenous malformations (AVM) of the skin, mucosa, and viscera. Epistaxis is the most frequent presentation. Visceral involvement includes pulmonary, gastrointestinal, and cerebral AVMs, which have been reported predominantly in adults. The purpose of this article is to describe 9 children who presented with intracranial hemorrhage (ICH) secondary to cerebral AVM. None of these children was suspected of having HHT before the incident, despite family histories of the disease.We report the first case of an ICH secondary to a cerebral AVM in a neonate confirmed to have HHT type 1 by molecular analysis. We also describe a series of 8 additional cases of ICH secondary to cerebral AVM in children presumed to have HHT. Examination of multiple affected members from each of these families, using well-accepted published criteria, confirmed the diagnosis of HHT. In addition, genetic linkage studies and/or mutation analysis identified endoglin as the disease-causing gene in 6 of these families. Autopsy, imaging studies, and/or surgery confirmed the presence of cerebral AVMs and ICH in all 9 cases.Our report shows that infants and children with a family history of HHT are at risk for sudden and catastrophic ICH. A preemptive diagnosis may potentially identify and prevent more serious sequelae.

View details for Web of Science ID 000173006600012

View details for PubMedID 11773580

Abstract

We report a case of congenital hypomyelination neuropathy presenting at birth. The infant had generalized hypotonia and weakness. There was decreased respiratory effort along with a right phrenic nerve and left vocal cord paralyses. Tongue fasciculations were present. Deep tendon reflexes were absent in the upper extremities and hypoactive (1+) in the lower extremities. Magnetic resonance imaging of the head revealed no intracranial abnormalities, including normal cerebral myelination. Nerve conduction study showed absence of motor and sensory action potentials in the hands when the nerves in the upper limbs were stimulated. A motor response could be elicited only in the proximal leg muscles. Needle electromyography study was normal in the proximal limb muscles, but showed active denervation in the distal muscles of the arm and leg. These findings were thought to be consistent with a length-dependent sensorimotor peripheral polyneuropathy of axonal type with greater denervation of the distal muscles. A biopsy of the quadriceps muscle showed mild variability in fiber diameter, but no group typing or group atrophy. The muscle fibers showed no intrinsic abnormalities. Biopsy of the sural nerve showed scattered axons with very thin myelin sheaths. There was also a nearly complete loss of large diameter myelinated fibers. No onion bulb formations were noted. These findings were thought to be consistent with congenital hypomyelination neuropathy with a component of axonopathy. DNA analysis for identification of previously characterized mutations in the genes MPZ, PMP22, and EGR2 was negative. Several attempts at extubation failed and the infant became increasingly ventilator-dependent with increasing episodes of desaturation and hypercapnea. He also developed increasing weakness and decreased movement of all extremities. He underwent surgery at 2 months of age for placement of a gastrostomy tube and a tracheostomy. He was discharged from the hospital on a ventilator at 6 months of age. The infant was 13 months old at the time of submission of this report. Although he appears cognitively normal, he remains profoundly hypotonic and is on a home ventilator. There was no evidence of progressive weakness. Congenital hypomyelination neuropathy is a rare form of neonatal neuropathy that should be considered in the differential diagnosis of a newborn with profound hypotonia and weakness. It appears to be a heterogeneous disorder with some of the cases being caused by specific genetic mutations.

View details for Web of Science ID 000171925200018

View details for PubMedID 11694679

Abstract

We screened 120 children with sporadic multiple congenital anomalies and either growth or mental retardation for uniparental disomy (UPD) or subtelomeric deletions. The screening used short tandem repeat polymorphisms (STRP) from the subtelomeric regions of 41 chromosome arms. Uninformative marker results were reanalyzed by using the next available marker on that chromosome arm. In total, approximately 25,000 genotypes were generated and analyzed for this study. Subtelomeric deletions of 1 Mb in size were excluded for 27 of 40 chromosome arms. Among the 120 subjects none was found to have UPD, but five subjects (4%, 95% confidence interval 1-9%) were found to have a deletion or duplication of one or more chromosome arms. We conclude that UPD is not a frequent cause of undiagnosed multiple congenital anomaly syndrome. In addition, we determined that 9p and 7q harbor chromosome length variations in the normal population. We conclude that subtelomeric marker analysis is effective for the detection of subtelomeric duplications and deletions, although it is labor intensive. Given a detection rate that is similar to prior studies and the large workload imposed by STRPs, we conclude that STRPs are an effective, but impractical, approach to the determination of segmental aneusomy given current technology.

View details for Web of Science ID 000171655300010

View details for PubMedID 11702212

View details for Web of Science ID 000166215500011

View details for PubMedID 11332402

Abstract

We report the first observation of parent-to-child transmission of dysgnathia, a rare disorder characterized by severe mandibular hypoplasia or agenesis, ear anomalies, microstomia, and microglossia. Patient 1 was noted prenatally by ultrasound to have severe micrognathia and, after birth, abnormal ears with canal stenosis and non-contiguous lobules located dorsally to the rest of the pinnae, normal zygomata, severe jaw immobility and microstomia with an opening of only 4 to 5 mm, hypoplastic tongue, and cleft palate. The 21-year-old mother of patient 1 was born with severe micrognathia requiring tracheostomy, microglossia, cleft palate with filiform alveolar bands, abnormal pinnae, and decreased conductive hearing. Dysgnathia is thought to result from a defect in the development of the first branchial arch. A similar phenotype has been seen in Otx2 haplo-insufficiency and endothelin-1 homozygous null mice, suggesting that these genes contribute to branchial arch development. Our report of a long-surviving mother and her daughter with non-syndromal dysgnathia may lead to identification of the molecular basis of these findings and provide insight into the genetics of first branchial arch formation. The survival of patient 1 and patient 2 beyond the neonatal period has implications for improvements in prenatal diagnosis and counseling and for neonatal treatment of this condition.

View details for Web of Science ID 000090115100014

View details for PubMedID 11102934

Abstract

For the past 22 years the interns in pediatrics at the University of Washington and Children's Hospital and Regional Medical Center have been relieved of all clinical duties in order to participate in a five-day retreat. The retreat provides an opportunity for the interns to learn more about their classmates, build stronger bonds, and provide mutual support. This retreat has been supported by the hospital, the department of pediatrics, faculty, fellows, and community physicians. The authors describe the history of the Intern Retreat, present its goals, daily activities, and faculty, and discuss how the retreat is funded and supported by the hospital and the medical community.

View details for Web of Science ID 000088739800020

View details for PubMedID 10965868

Abstract

Chromosomal aberrations are a common cause of multiple anomaly syndromes that include developmental and growth retardation. Current microscopic techniques are useful for the detection of such aberrations but have a limit of resolution that is above the threshold for phenotypic effect. We hypothesized that a genomewide microsatellite screen could detect chromosomal aberrations that were not detected by standard cytogenetic techniques in a portion of these individuals. To test this hypothesis, we performed a genomewide microsatellite screen of patients, by use of a currently available genetic-marker panel that was originally designed for meiotic mapping of Mendelian traits. We genotyped approximately 400 markers on 17 pairs of parents and their children who had normal karyotypes. By using this approach, we detected and confirmed two cases of segmental aneusomy among 11 children with multiple congenital anomalies. These data demonstrate that a genomewide microsatellite scan can be used to detect chromosomal aberrations that are not detected by microscopic techniques.

View details for Web of Science ID 000088373100008

View details for PubMedID 10677301

Abstract

To determine current practices of genetic counseling and screening for consanguineous couples, their pregnancies and children, and to compare these practices to recommendations in the literature.A questionnaire was mailed to 1,582 board certified genetic counselors and medical geneticists in the United States.The return rate was 20% (n = 309). There was wide variation in the risk figures quoted to consanguineous couples to have offspring with birth defects and mental retardation (1% to 75% for incest between first-degree relatives, and 0.25% to 20% for first cousin unions). Suggested screening practices differed for consanguineous unions before conception, during pregnancy, following birth, and for children placed for adoption. Most respondents recommended screening based on ethnicity, yet disagreed as to which genetic disorders to include.To standardize genetic services, guidelines for screening the offspring of consanguineous unions are needed. A consensus should be reached as to the empirical risks for genetic disorders, birth defects, and mental retardation that may impair the offspring of consanguineous unions, with definition as to what these disorders are, and if the data applies to global populations. Guidelines should consider costs, the sensitivity and specificity of DNA and biochemical testing, and current practices of prenatal and newborn screening. Consideration should be given to screening based on ethnicity, particularly in populations where consanguineous unions are common, while remaining sensitive to cultural belief systems. Recommendations for screening healthy children from consanguineous unions to be placed for adoption pose ethical challenges.

View details for Web of Science ID 000084590600008

View details for PubMedID 11258630

Abstract

To report the phenotypic spectrum and management issues of children with Kabuki syndrome (Niikawa-Kuroki syndrome) from North America.A case series of children (n = 18) with clinical findings of Kabuki syndrome.Medical genetics clinics in Washington, Alaska, and Arizona.Most patients had postnatal growth retardation, and all had developmental delay and hypotonia. Feeding difficulties, with or without cleft palate, were common; 5 patients required gastrostomy tube placement. Developmental quotients/IQs in all but 2 were 60 or less. Seizures were seen in less than half of the patients, but ophthalmologic and otologic problems were common, particularly recurrent otitis media. Congenital heart defects were present in 7 (39%); 3 patients underwent repair of coarctation of the aorta. Other features included urinary tract anomalies, malabsorption, joint hypermobility and dislocation, congenital hypothyroidism, idiopathic thrombocytopenic purpura, and in one patient, autoimmune hemolytic anemia and hypogammaglobulinemia. All patients had negative family histories for Kabuki syndrome.Kabuki syndrome is a mental retardation-malformation syndrome affecting multiple organ systems, with a broad spectrum of neuromuscular dysfunction and mental ability. Given that 18 ethnically diverse patients were identified from 2 genetics programs, it appears that this syndrome is more common in North American non-Japanese patients than previously appreciated.

View details for Web of Science ID 000079648400016

View details for PubMedID 10190924

Abstract

The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates members of the transforming growth factor beta superfamily of signalling proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a principal role in creating morphogenic gradients. During mouse embryogenesis, Nog is expressed at multiple sites, including developing bones. Nog-/- mice die at birth from multiple defects that include bony fusion of the appendicular skeleton. We have identified five dominant human NOG mutations in unrelated families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo mutation in a patient with unaffected parents. We also found a dominant NOG mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM 186500); both SYM1 and SYNS1 have multiple joint fusion as their principal feature. All seven NOG mutations alter evolutionarily conserved amino acid residues. The findings reported here confirm that NOG is essential for joint formation and suggest that NOG requirements during skeletogenesis differ between species and between specific skeletal elements within species.

View details for Web of Science ID 000078977900025

View details for PubMedID 10080184

Abstract

We report on a three-generation family with "expansile" bone lesions of the distal radius and ulna, cortical thickening of the proximal long bones, and pathologic fractures. The differential diagnosis of expansile bone lesions includes isolated bone cysts and tumors, such as enchondromas and fibrous dysplasia; familial expansile osteolysis; and the genochondromatoses. Our patients have findings most similar to the genochondromatoses; however, the distribution of the lesions and the accompanying manifestations may be evidence for a unique genetic condition in this family.

View details for Web of Science ID 000078009200001

View details for PubMedID 9916834

Abstract

We report on 10 African Americans with Prader-Willi syndrome whose features differ from those of white patients with this condition. Growth is less affected, hand and foot lengths usually are normal, and the facies are atypical; this may lead to underdiagnosis in this population. We encourage clinicians to recognize these phenotypic differences so that diagnosis is not overlooked.

View details for Web of Science ID 000082704300010

View details for PubMedID 11261430

Abstract

Shprintzen-Goldberg syndrome is one of a group of disorders characterized by craniosynostosis and marfanoid habitus. Eleven cases were reported previously. We present 4 new patients and review one of the patients of the original report of Shprintzen and Goldberg [1982: J Craniofac Genet Dev Biol 2:65-74], 15 years later. The clinical and radiologic findings on our patients are compared with those of the previously reported patients and also with those of Furlong et al. [1987: Am J Med Genet 26:599-604] and Lacombe and Battin [1993: Clin Dysmorphol 2: 220-224], who share many of the characteristics of Shprintzen-Goldberg syndrome. Some of the clinical data are helpful in determining if the patients of Furlong et al. [1987: Am J Med Genet 26:599-604] and Lacombe and Battin [1993: Clin Dysmorphol 2: 220-224] have a separate syndrome or represent a variant of Shprintzen-Goldberg syndrome. However, radiologic investigations appear to be more specific, since an abnormality of the first and second cervical vertebrae, hydrocephalus, dilatation of the lateral ventricles, and a Chiari-I malformation of the brain were found only in the patients with Shprintzen-Goldberg syndrome. The apparently diagnostic findings of the 15 patients with this syndrome may be helpful in differentiating between Shprintzen-Goldberg syndrome and other syndromes with craniosynostosis and marfanoid habitus.

View details for Web of Science ID 000072292400002

View details for PubMedID 9508238

Abstract

We present four patients-two boys and their mother and an unrelated girl-with microcephaly, normal intelligence, and digital abnormalities. The hand abnormalities are characterized by brachydactyly with radial clinodactyly of the fourth and fifth fingers, ulnar clinodactyly of the second fingers, and an increased space between the second and third fingers associated with an abnormal palmar crease that extends to the ulnar border. The foot abnormalities include short toes with syndactyly of the fourth and fifth toes. The mother has normal intelligence, and her sons and the unrelated girl have normal development. Although similar digital abnormalities, microcephaly, and normal intelligence were described by Feingold in patients with gastrointestinal atresia, we think that our patients' findings represent a different condition. The most likely mode of inheritance is autosomal dominant. The clinical recognition of this syndrome will allow for appropriate genetic counseling as well as provision of information on natural history, i.e., normal intelligence.

View details for Web of Science ID A1997WQ31400006

View details for PubMedID 9096751

Abstract

Split hand/split foot malformation (SHFM) is a heterogeneous limb developmental disorder, characterized by missing digits and fusion of remaining digits. An autosomal dominant form of this disorder (SHFM1) has been mapped to 7q21.3-q22.1 on the basis of SHFM-associated chromosomal rearrangements. Utilizing a YAC contig across this region, we have defined a critical interval of 1.5 Mb by the analysis of six interstitial deletion patients and mapped the translocation breakpoints of seven ectrodactyly patients within the interval. To delineate the basic molecular defect underlying SHFM, we have searched for candidate genes in a 500 kb region containing five of the translocation breakpoints. Three genes were identified, two genes of the Distal-less (dii) homeobox gene family, DLX5 and DLX6 and a novel gene, which we named DSS1. DSS1 is predicted to encode a highly acidic polypeptide with no significant similarity to any known proteins but 100% amino acid sequence identify with its murine homolog (Dss1). Using RNA in situ hybridization analysis, we detected a tissue-specific expression profile for Dss1 in limb bud, craniofacial primordia and skin. A deficiency in expression of Dss1, DLX5 and/or DLX6 during development may explain the SHFM phenotypes.

View details for Web of Science ID A1996UJ74300002

View details for PubMedID 8733122

Abstract

New information has been obtained on 30 patients with isolated persistent hypermethioninemia, most of them previously unreported. Biopsies to confirm the presumptive diagnosis of partially deficient activity of ATP: L-methionine S-adenosyltransferase (MAT; E.C.2.5.1.6) in liver were not performed on most of these patients. However, none showed the clinical findings or the extreme elevations of serum folate previously described in other patients with isolated hypermethioninemia considered not to have hepatic MAT deficiency. Patients ascertained on biochemical grounds had no neurological abnormalities, and 27/30 had IQs or Bayley development-index scores within normal limits or were judged to have normal mental development. Methionine transamination metabolites accumulated abnormally only when plasma methionine concentrations exceeded 300-350 microM and did so more markedly after 0.9 years of age. Data were obtained on urinary organic acids as well as plasma creatinine concentrations. Patterns of inheritance of isolated hypermethioninemia were variable. Considerations as to the optimal management of this group of patients are discussed.

View details for Web of Science ID A1995RV79300020

View details for PubMedID 7573050

Abstract

In an effort to identify regions on chromosome 18 that may be critical in the appearance of the Edwards syndrome phenotype, we have analyzed six patients with partial duplication of chromosome 18. Four of the patients have duplications involving the distal half of 18q (18q21.1-qter) and are very mildly affected. The remaining two patients have most of 18q (18q12.1-qter) duplicated, are severely affected, and have been diagnosed with Edwards syndrome. We have employed FISH, using DNA probes from a chromosome 18-specific library, for the precise determination of the duplicated material in each of these patients. The clinical features and the extent of the chromosomal duplication in these patients were compared with four previously reported partial trisomy 18 patients, to identify regions of chromosome 18 that may be responsible for certain clinical features of trisomy 18. The comparative analysis confirmed that there is no single region on 18q that is sufficient to produce the trisomy 18 phenotype and identified two regions on 18q that may work in conjunction to produce the Edwards syndrome phenotype. In addition, correlative analysis indicates that duplication of 18q12.3-q22.1 may be associated with more severe mental retardation in trisomy 18 individuals.

View details for Web of Science ID A1994PF50900009

View details for PubMedID 8079991

Abstract

Down syndrome (DS) is a major cause of mental retardation and congenital heart disease. Besides a characteristic set of facial and physical features, DS is associated with congenital anomalies of the gastrointestinal tract, an increased risk of leukemia, immune system defects, and an Alzheimer-like dementia. Moreover, DS is a model for the study of human aneuploidy. Although usually caused by the presence of an extra chromosome 21, subsets of the phenotypic features of DS may be caused by the duplication of small regions of the chromosome. The physical map of chromosome 21 allows the molecular definition of the regions duplicated in these rare cases of partial trisomy. As a first step in identifying the genes responsible for individual DS features and their pathophysiology, a panel of cell lines derived from 16 such individuals has been established and the molecular break points have been determined using fluorescence in situ hybridization and Southern blot dosage analysis of 32 markers unique to human chromosome 21. Combining this information with detailed clinical evaluations of these patients, we have now constructed a "phenotypic map" that includes 25 features and assigns regions of 2-20 megabases as likely to contain the genes responsible. This study provides evidence for a significant contribution of genes outside the D21S55 region to the DS phenotypes, including the facies, microcephaly, short stature, hypotonia, abnormal dermatoglyphics, and mental retardation. This strongly suggests DS is a contiguous gene syndrome and augurs against a single DS chromosomal region responsible for most of the DS phenotypic features.

View details for Web of Science ID A1994NN21400082

View details for PubMedID 8197171

Abstract

Spondylothoracic dysostosis, or Jarcho-Levin syndrome, together with spondylocostal dysostosis, constitute a heterogeneous group of rare disorders characterized by short-neck, short-trunk dwarfism and multiple vertebral anomalies at all levels of the vertebral column. The latter include hemivertebrae, fused, hypoplastic, and "butterfly" vertebrae. In most cases of Jarcho-Levin syndrome, the small size of the thorax causes respiratory death in infancy. This report of a Puerto Rican child with spondylothoracic dysostosis and unusually long survival to 11 years exemplifies the nosologic and prognostic difficulties associated with this syndrome.

View details for Web of Science ID A1994MT95300016

View details for PubMedID 8209895

Abstract

Staphylococcus aureus and group A Streptococcus pyogenes produce toxic shock syndrome characterized by hypotension and multisystem organ failure. While conventional therapy has consisted of antibiotics and intensive supportive care, some experimental evidence suggests that immunoglobulins directed against the toxins may be effective additional therapy. We report a case of "toxic strep syndrome" in which intravenous immunoglobulin was administered when signs and symptoms were worsening while the patient was receiving conventional therapy. Within hours of administration of the intravenous immunoglobulin, the patient experienced dramatic clinical improvement. This response suggests a possible therapeutic benefit of intravenous immunoglobulin in toxic shock syndrome.

View details for Web of Science ID A1992HY94400031

View details for PubMedID 1597914

Abstract

Two siblings with Jeune thoracic dystrophy had persistent evidence of hepatic dysfunction; one had cirrhosis. Liver disease, a significant problem in patients who survive this condition, may be progressive in some.

View details for Web of Science ID A1992HT98100016

View details for PubMedID 1578311

Abstract

Small hands and feet (acromicria) are often cited as manifestations in the Prader-Willi syndrome (PWS), but it has been our experience that these are not universal findings. To address this issue, we obtained longitudinal and cross-sectional data, retrospectively and prospectively, including height, hand length, and foot length, on 56 patients with PWS who are followed in the multidisciplinary PWS clinic at the University of Connecticut Health Center. Hand and foot lengths were plotted using two published sets of normative data. In addition, height age was calculated on each measurement of stature so that the corresponding hand and foot measurements could be compared to those expected for height, rather than age, as many PWS individuals are short. Foot length was proportionately smaller than hand length in all individuals; this difference was more striking in females. By age 12 years, almost all individuals had a foot length less than 25th centile for chronological age and less than 50th centile for height age. Female hand length was also less than 25th centile for chronological by age 12 years and less than 50th centile for height age in almost all cases. Male hand length data appeared to fall more within the normal range until adulthood, although fewer data were available. Black individuals with PWS had relatively larger hands and feet than their Caucasian counterparts. Many people with PWS had hand and foot lengths which fell within the normal range, particularly those under the age of 12 years and those whose height was greater than 50th centile for age.(ABSTRACT TRUNCATED AT 250 WORDS)

View details for Web of Science ID A1991GH55200002

View details for PubMedID 1951464

Abstract

We have analysed 40 marker loci on 13 chromosomes for linkage with Marfan syndrome. None of the loci was linked to the Marfan syndrome locus at theta = 0.00. This study provides a basis for an exclusion map and for further collaboration in mapping of the locus.

View details for Web of Science ID A1990CM25600004

View details for PubMedID 1969490