Recent Publications & Updates

Quickly discover all publications on Dr. Tamar Green’s Google Scholar page.

Tamar Green
Associate Professor of Psychiatry and Behavioral Sciences (Interdisciplinary Brain Sciences) and, by courtesy, of Pediatrics

Publications

  • Genotype-phenotype correlations with autism spectrum disorder-related traits in noonan syndrome and noonan syndrome with multiple lentigines: a cross-sectional study. Molecular autism McGhee, C. A., Plank, J. R., Pannone, L., Russo, O., Fuhrmann, N., Ruggeri, A., Radio, F. C., Martinelli, S., Tartaglia, M., Green, T. 2025; 16 (1): 51

    Abstract

    Noonan syndrome (NS) and Noonan syndrome with multiple lentigines (NSML) are neurodevelopmental conditions caused by genetic variants leading to upregulated signaling in the RAS-MAPK pathway. While previous research has focused on genetic variability in cognitive and cardiac phenotypes, behavioral phenotypes, and their correlations across genetic variants and within the PTPN11 gene remain poorly characterized.This study included 121 individuals with NS (PTPN11: 88, SOS1: 18, RAF1: 6, KRAS: 2, RIT1: 3, NRAS: 2, LZTR1: 2, SOS2: 1) and seven individuals with NSML (PTPN11), compared to age- and sex-matched typically developing (TD) (N = 71). Behavioral questionnaires assessed social responsiveness and ASD-related traits (using SRS-2), and emotional problems (using CBCL) to identify genetic variant-specific behavioral profiles. Biochemical profiling of SHP2 activity in PTPN11-associated NS variants examined genotype-phenotype relationships.Compared to TD individuals, those with PTPN11-associated NS, NSML, and SOS1-associated NS exhibited clinically elevated scores, indicating increased ASD-related behaviors, poorer social functioning, and heightened emotional problems. Genetic variant comparisons revealed that individuals with PTPN11-associated NS and NSML exhibited greater ASD-related challenges than those with RAF1. Individuals with NSML exhibit elevated attention problems compared to all other genetic groups. Logistic regression results suggested each one-unit increase in SHP2 fold activation for PTPN11-associated NS corresponded to a 64% higher likelihood of markedly elevated restricted and repetitive behaviors, suggesting genotype-phenotype links.Small sample sizes for rarer variants, leading to unequal group sizes across subgroups, with PTPN11 variants comprising most of the NS group. Future research should address these sampling constraints and conduct functional studies to clarify variant impacts. Longitudinal assessments could elucidate behavioral phenotype trajectories.This study underscores the importance of genetic variant-specific research to understand unique behavioral phenotypes in NS and NSML. Our findings indicate a higher risk for ASD-related symptoms in PTPN11-associated NS and NSML compared to other variants. Additionally, individuals with PTPN11-associated NS and higher SHP2 fold activation exhibited greater impairments in restricted and repetitive behaviors, suggesting SHP2 activation variations may contribute to phenotypic variability. By linking ASD-related symptoms to biochemical predictors in PTPN11-associated NS, this study may inform future targeted treatment approaches.

    View details for DOI 10.1186/s13229-025-00681-1

    View details for PubMedID 41074228

    View details for PubMedCentralID PMC12514806

  • Transdiagnostic similarities and distinctions in brain networks associated with ASD symptoms: A prospective cohort study. medRxiv : the preprint server for health sciences Bruno, J. L., Plank, J. R., Leder, S., Lake, E. M., Finn, E. S., Green, T. 2025

    Abstract

    Background: Despite high rates of autism spectrum disorder (ASD), understanding of pathophysiology is limited. The RAS-mitogen-activated protein kinase (RAS-MAPK) pathway plays a crucial role in ASD and is altered in children with Noonan syndrome (NS). Children with NS offer a unique model to disentangle genetic and neurological underpinnings of ASD.Methods: This study aimed to examine functional brain network anatomy underlying ASD symptoms in children with NS (n=28, mean age=8.24), and tested generalizability of models developed in a non-syndromic cohort enriched for ASD (Autism Brain Imaging Data Exchange (ABIDE), n=352, mean age=11.0). Connectome-based predictive modeling (CPM) was applied to fMRI data to predict the severity of autism symptoms, indexed by the Social Responsive Scale (SRS), in children with NS. Next, we tested if a model developed to predict autism symptoms in an autism-enriched sample of children without genetic diagnosis (ABIDE) could predict autism symptoms in children with NS.Results: Predicted SRS scores were significantly associated with observed SRS scores in NS (r s =0.43, p=.011). Application of the predictive model generated in the autism-enriched cohort (ABIDE) significantly predicted observed SRS scores in NS (r s =0.460, p=.018). Predictive brain networks in both NS and the non-syndromic cohorts included subcortical-cerebellar networks and visual processing networks.Limitations: The size of our NS cohort is small, given the rarity of NS. However, the significant cross-dataset comparison yielded in this study suggests that use of large publicly available datasets can be useful in contextualizing smaller and harder to collect datasets in rare genetic syndromes.Conclusions: The presence of shared brain networks suggests a converging pattern of functional connectivity underlying autism symptoms, irrespective of genetic diagnosis. Evidence of shared brain networks in children with idiopathic autism and NS highlights the role of RAS-MAPK in autism symptoms and points to the value of leveraging human genetic models to enhance our understanding of idiopathic ASD.

    View details for DOI 10.1101/2025.09.17.25336005

    View details for PubMedID 41001444

  • T1w/T2w ratio suggests reduced intracortical myelin content in youth with RASopathies. medRxiv : the preprint server for health sciences Plank, J. R., Pardej, S. K., Raman, M. M., McNab, J., Green, T. 2025

    Abstract

    Background Myelin may represent a modifiable treatment target in neurodevelopmental disorders, however, a reliable tool for in vivo assessment of myelin alterations in clinical settings is needed. Prior work shows commonly acquired T1-weighted (T1w) and T2-weighted (T2w) scans can be transformed into ratio maps and subsequently provide a reasonable estimate of cortical myelin content. We investigated T1w/T2w ratios for measuring cortical myelin in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway. Methods In this prospective study, 112 children (86 RASopathies, 26 typical developing (TD), aged 6-17 years) completed T1w and T2w MRI scans and NIH Toolbox cognitive assessments. Parent-rated mobility and strength impact scores were also acquired. T1w/T2w ratio maps were calculated at three levels of the cortex in FreeSurfer, and average values were extracted from 68 regions-of-interest (ROIs) at each level across the brain and from eight subcortical ROIs. Group differences were assessed using analyses of covariance, including a false discovery rate adjustment for multiple comparisons. As an exploratory analysis, differences in cognitive scores and parent-rated health were assessed across quartiles of whole-brain T1w/T2w ratios. Results Widespread decreases in T1w/T2w ratios were found in the RASopathies group, suggesting decreased cortical myelin content. Of the T1w/T2w ratios sampled along the midline, 63 of 68 cortical ROIs were significantly reduced in RASopathies (pFDR<.050). Of the subcortical ROIs, only the T1w/T2w ratio in the accumbens was significantly reduced in RASopathies compared to TD (Cohens d=0.520, pFDR=.024). Exploratory quartile analyses across the whole sample indicated significant effects of T1w/T2w ratio quartile on mobility (p=.002) and strength impact ratings (p<.001), such that subjects in higher T1w/T2w ratio quartiles had better physical health ratings. Conclusions These results support the utility of T1w/T2w ratio mapping as a sensitive tool for detecting cortical myelin alterations in genetically defined neurodevelopmental disorders. Exploratory analyses suggest a relationship between cortical myelin content and physical mobility and stamina. Future work should explore the clinical relevance of these findings for cognitive and functional outcomes and assess their potential as biomarkers for targeted therapeutic interventions.

    View details for DOI 10.1101/2025.09.16.25335916

    View details for PubMedID 41001496

  • Subcortical shape alterations in children with Noonan syndrome spectrum: insights into genotype-phenotype associations. Cerebral cortex (New York, N.Y. : 1991) Serur, Y., McGhee, C. A., Avital, N., Russo, O., Raman, M. M., Green, T. 2025; 35 (8)

    Abstract

    Noonan syndrome is the most common RASopathy and is associated with high rates of neurodevelopmental disorders. Prior neuroimaging studies in children with Noonan syndrome have identified structural effects on subcortical regions, though most focus on volumetric differences, overlooking finer morphological changes. These studies also tend to examine common genetic variants, excluding rarer forms within the Noonan syndrome spectrum. Shape analysis offers a sensitive approach to detecting subtle alterations, and when applied across variants, may reveal distinct neuroanatomical signatures. We acquired anatomical magnetic resonance imaging scans from 104 children with Noonan syndrome spectrum (ages 5 to 17, mean = 10.0) and 80 age- and sex-matched typically developing children (ages 4 to 16, mean = 9.54). Our comprehensive analysis examined local thickness and surface dilation/contraction (Jacobian), including genetic variant-specific analyses. Noonan syndrome spectrum showed widespread subcortical alterations beyond volume reduction, including thinning and surface contraction in the putamen, pallidum, thalamus, and caudate, and expansion in the accumbens. Distinct regional effects were found for PTPN11, SOS1, and other Noonan syndrome spectrum-associated variants. These findings confirm subcortical volume reductions in several regions and highlight complex, region-specific shape alterations. Importantly, neuroanatomical patterns varied across genetic variants, suggesting distinct mechanisms of brain development. Understanding these variant-specific structural profiles may provide insights into genotype-based approaches and inform future precision medicine strategies.

    View details for DOI 10.1093/cercor/bhaf217

    View details for PubMedID 40801889

  • Increased Prevalence of Psychiatric Disorders in Children with RASopathies: Comparing NF1, Noonan Syndrome Spectrum Disorder, and the General Population. Genes Serur, Y., Russo, O., McGhee, C. A., Green, T. 2025; 16 (7)

    Abstract

    Background/Objectives: Neurofibromatosis type 1 (NF1) and Noonan syndrome spectrum disorders (NSSD) are the most common RASopathies, resulting from germline mutations that affect the RAS-MAPK signaling pathway. Both are associated with increased risk for neurodevelopmental and psychiatric conditions, yet few studies have used structured diagnostic interviews to compare their psychiatric comorbidities. Methods: We conducted clinician-administered DSM-5 diagnostic assessments (KSADS) in 123 children with RASopathies (NF1 = 29, NSSD = 94; ages 5-15). Diagnosis prevalence was compared within each group and to population-based estimates. Results: Psychiatric diagnoses were highly prevalent, at 79.3% in NF1 and 76.6% in NSSD, with ADHD (NF1 = 72.4%, NSSD = 51.1%) and anxiety disorders (NF1 = 37.9% and NSSD = 43.6%) being the most common, rates substantially higher than those reported in general population estimates. Behavioral and sleep disorders were identified in approximately 25% of both groups. Notably, social anxiety disorder was identified in 14.9% of NSSD but not in NF1. Full-scale IQ did not significantly differ by diagnosis status. Specific anxiety disorders, elimination disorders, obsessive-compulsive disorder, and post-traumatic stress disorder were characterized, expanding the known psychiatric phenotype of RASopathies. Conclusions: Children with NF1 and NSSD demonstrate similarly high rates of ADHD, anxiety, and behavioral disorders compared to the general population; in addition, we report sleep disorders in NSSD and characterize psychiatric disorders not previously described in RASopathies. The shared psychiatric profiles may reflect the common effect of RAS-MAPK pathway dysregulation on psychiatric outcomes. These findings highlight the need for early, syndrome-informed mental health screening and intervention in the clinical care of individuals with RASopathies.

    View details for DOI 10.3390/genes16070843

    View details for PubMedID 40725498

  • Irritability in children with RASopathies, insights into emotional dysregulation and social impairment. European child & adolescent psychiatry Serur, Y., Fuhrmann, N., Russo, O., Green, T. 2025

    View details for DOI 10.1007/s00787-025-02767-w

    View details for PubMedID 40459753

  • Quantitative T1 mapping indicates elevated white matter myelin in children with RASopathies. Biological psychiatry Plank, J. R., Gozdas, E., Bruno, J., McGhee, C. A., Wu, H., Raman, M. M., Saggar, M., Green, T. 2025

    Abstract

    Evidence suggests a pathological role of myelination in neurodevelopmental disorders with links to cognitive difficulties, but in vivo assessment remains challenging. Quantitative T1 mapping (QT1) has been used in prior clinical studies (e.g., of multiple sclerosis) and shows promise for reliable measurement of myelin alterations. We investigated QT1 for measuring myelination in children with neurodevelopmental disorders of the RAS-MAPK signaling pathway (RASopathies).We collected QT1, diffusion-weighted, and structural MRI scans from 72 children (49 RASopathies, 23 typical developing (TD)). QT1 myelin content measures included white matter macromolecular tissue volume (MTV) and cortical R1 (1/T1 relaxation). Group differences were assessed across 39 white matter tracts. Principal components analysis captured cortical myelination patterns across 360 regions, followed by a MANOVA. A support vector machine (SVM) identified the most discriminative features between-groups.Thirty-four of 39 tracts were higher in MTV in RASopathies relative to TD (pFDR<.05), indicating widespread elevation in myelination. MANOVA revealed a group effect on cortical R1 (p=.002, η2=.028), suggesting cortical myelination differences between-groups. The SVM yielded an accuracy of 87% and identified cognitive and cortical R1 features as the most discriminant between-groups.We found widespread elevated white matter tract myelin and region-dependent cortical myelination patterns in children with RASopathies. Leveraging preclinical models showing oligodendrocyte dysfunction, QT1 revealed precocious myelination. Further work is needed to explore relationships with cognition. QT1 is a promising tool for identification and monitoring of myelin as a treatment target in neurodevelopmental disorders, offering significant potential for advancing current therapeutic strategies.

    View details for DOI 10.1016/j.biopsych.2025.04.014

    View details for PubMedID 40316128

  • A familial modeling framework for advancing precision medicine for children with neuropsychiatric disorders. Developmental medicine and child neurology Bruno, J. L., Merrin, J. J., Hosseini, S. M., Green, T. 2025

    Abstract

    To provide individualized estimates of expected child neuropsychiatric and neuroanatomical outcomes by using parent cognitive and behavioral traits in a predictive framework.Predictive modeling was applied to 52 families of children with Noonan syndrome, a neurogenetic syndrome affecting the Ras/mitogen-activated protein kinase (MAPK) pathway.Parent cognition (specifically visuospatial and motor abilities), depression, anxiety, and attention-deficit/hyperactivity disorder symptoms were significantly associated with child outcomes in these domains. Parent cognition was also significantly associated with child neuroanatomical variability. The middle temporal cortex was weighted strongly in the model predicting child neuroanatomy and not identified in previous work, but was correlated with parent cognition, suggesting a larger familial effect in this region.Using parent traits provides a more individualized estimate of expected child cognitive, behavioral, and neuroanatomical outcomes. Understanding how parent traits influence neuroanatomical outcomes helps to further a mechanistic understanding of the impact of Ras/MAPK on neurodevelopmental outcomes. Further refinement of predictive modeling to estimate individualized child outcomes will advance a precision medicine approach to treating Noonan syndrome, other neurogenetic syndromes, and neuropsychiatric disorders more broadly.

    View details for DOI 10.1111/dmcn.16278

    View details for PubMedID 40119877