Current Research and Scholarly Interests
More than 1200 sequence variants have been described in the CFTR gene to date. Following recommendations by the American College of Medical Genetics and the American College of Obstetrics and Gynecology, mutation screening has become the standard of care for anyone who considers having children. The panel used most often for screening and diagnostic testing is severely biased towards Caucasians and although more comprehensive testing is available, it is not offered widely. In order to reduce the discrepancy in mutation detection between Caucasian individuals and those of other or mixed extraction, we (in collaboration with the Gardner laboratory and Asper) developed a rapid, highly sensitive and affordable diagnostic and research arrayed primer extension assay suitable for both diagnostic and screening use in multiple racial and ethnic groups, worldwide. Additional research is underway in the Schrijver laboratory to adequately map the mutation composition and individual frequencies in many previously understudied populations. However, this panel is expected to significantly raise the mutation detection ability above any currently commercially available diagnostic panel with a set number of detectable mutations. The APEX CF assay enables high-throughput testing at low cost on an individual basis and allows flexibility for future addition of mutations. Such improved diagnostics are expected to allow patient-tailored prognosis, treatment, and family-specific genetic counseling.
Sensorineural hearing loss
Tremendous progress has been made in our understanding of the molecular basis of hearing and hearing loss. Through recent advances, the fascinating biology of the auditory system and new molecular mechanisms of hearing impairment have begun to be unveiled. Changes in the diagnostic impact of genetic testing have occurred, as well as exciting developments in therapeutic options (such as cochlear implants). Molecular diagnosis, which is already a reality for several hearing-associated genes, will continue to increase in the near future, both in terms of the number of mutations tested and the spectrum of genes. Inherited hearing loss, however, is characterized by impressive genetic heterogeneity. An abundance of genes carry a large number of mutations, but specific mutations in a single gene may lead to syndromic or nonsyndromic hearing loss. Some mutations predominate in individual ethnic groups. We (Schrijver and Gardner laboratories) have developed a sensorineural hearing loss APEX array. The Schrijver laboratory is also investigating genotype-phenotype correlations and pathogenic mechanisms for several hearing loss-associated genes (connexins, SLC26A4, others).
Mitochondrial mutation detection
Currently, ~150 mtDNA mutations are known, most of which are present in tRNAs. Using DHPLC, we screen the entire mitochondrial genome for heteroplasmic mutations in patients for whom a molecular basis for disease has not yet been identified. Individual mutations are characterized by follow-up DNA sequencing. We are aiming to ultimately elucidate genotype-phenotype correlations. For example, MERRF and MELAS can be caused by the same mutations but it remains unknown why the clinical phenotypes are different. Our current research is focused on a group of patients with hypertrophic cardiomyopathy, patients with sensorineural hearing loss, and patients with a phenotype highly suspicious of a mitochondrial disorder. We aim to find new mutations in tRNAs, new mutations in protein coding genes, and to elucidate possible pathogenicity of homoplasmic mutations through influences of the environment, haplotype, nuclear background, and tissue specific expression of interacting genes. We are also interested in the significance of haplotypes (as the constellation of SNPs may weaken Oxphos system).