Category Ranking
98%
Total Visits
921
Avg Visit Duration
2 minutes
Citations
20
Article Abstract
Purpose: The ClinGen RASopathy (RAS) Variant Curation Expert Panel (VCEP) previously established RASopathy specifications to the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) variant classification framework for more consistent and accurate variant classification. Advances in the understanding of RASopathies and new clinical genetic testing algorithms required updated specifications.
Methods: The RAS Gene Curation Expert Panel recurated 6 gene-disease relationships, and the RAS VCEP evaluated the previous specifications to develop updated RASopathy specifications for the ACMG/AMP framework. The performance of these updated specifications was tested by reassessing 59 previously classified variants and 88 new pilot variants.
Results: Five gene-disease relationships were upgraded to Definitive, whereas 1 was upgraded to Moderate. Updated specifications were applied to 11 ACMG/AMP criteria for disorders with a dominant inheritance, 3 criteria for recessive inheritance, and 4 criteria to align with recommendations from the ClinGen Sequence Variant Interpretation Working Group. Assessment of variants demonstrated no major shifts in classifications compared with previous RAS VCEP or ClinVar classifications.
Conclusion: Updated RASopathy specifications improve the classification of variants associated with recessive disease and observed in exome/genome cases. Most of these specifications may also be used as a baseline for other rare Mendelian disorders.
Download full-text PDF |
Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC12151217 | PMC |
| http://dx.doi.org/10.1016/j.gimo.2025.103430 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Subcortical shape alterations in children with Noonan syndrome spectrum: insights into genotype-phenotype associations.
Cereb Cortex
August 2025
Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Sciences, Stanford University, School of Medicine, 1520 Page Mill Road, Palo Alto, CA 94304, United States.
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.
View Article and Find Full Text PDFIncreased Prevalence of Psychiatric Disorders in Children with RASopathies: Comparing NF1, Noonan Syndrome Spectrum Disorder, and the General Population.
Genes (Basel)
July 2025
Division of Interdisciplinary Brain Sciences, Department of Psychiatry and Behavioral Science, School of Medicine, Stanford University, Stanford, CA 94305, USA.
: 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. We conducted clinician-administered DSM-5 diagnostic assessments (KSADS) in 123 children with RASopathies (NF1 = 29, NSSD = 94; ages 5-15).
View Article and Find Full Text PDFSerum Markers of Bone Turnover and Bone Remodeling in Children with Noonan Syndrome: Genotype-Phenotype Correlation.
Genes (Basel)
May 2025
Pediatric Unit, Department of Precision and Regenerative Medicine and Ionian Area, University "A. Moro", 70124 Bari, Italy.
Noonan syndrome (NS) is a genetic disorder characterized by distinctive craniofacial and skeletal features, short stature, mild to moderate developmental impairment, and multisystem involvement, notably affecting the cardiovascular, musculoskeletal, and endocrine systems. Although abnormalities of the bone matrix, as well as osteopenia and osteoporosis, are well recognized in individuals with NS and other RASopathies, the specific impact of RAS/MAPK pathway dysregulation on bone health remains poorly understood. The aim of this study was to evaluate bone turnover and bone remodeling markers in a cohort of children with NS, to gain further insights into the bone status of these patients.
View Article and Find Full Text PDFSecond Trimester Ultrasound Diagnosis of External Hydrocephalus in Two Fetuses with Noonan Syndrome-Case Report Series.
J Clin Med
June 2025
Department of Obstetrics and Gynecology, University of Szeged, H-6725 Szeged, Hungary.
Noonan syndrome (NS) is a relatively common RASopathy that can be associated with a variety of phenotypic and genotypic variations and potential long-term health consequences. Its most described prenatal ultrasound features in the first trimester are thickened nuchal translucency (NT) and dilated jugular sacs; while heart defects, polyhydramnios and facial dysmorphisms are its known manifestations in the second and third trimesters. We present two cases of NS with the prenatal ultrasound diagnosis of external hydrocephalus (EH) in the second trimester.
View Article and Find Full Text PDFUpdated ACMG/AMP specifications for variant interpretation and gene curations from the ClinGen RASopathy expert panels.
Genet Med Open
April 2025
Mass General Brigham, Laboratory for Molecular Medicine, Cambridge, MA.
Purpose: The ClinGen RASopathy (RAS) Variant Curation Expert Panel (VCEP) previously established RASopathy specifications to the American College of Medical Genetics and Genomics (ACMG) and Association of Molecular Pathology (AMP) variant classification framework for more consistent and accurate variant classification. Advances in the understanding of RASopathies and new clinical genetic testing algorithms required updated specifications.
Methods: The RAS Gene Curation Expert Panel recurated 6 gene-disease relationships, and the RAS VCEP evaluated the previous specifications to develop updated RASopathy specifications for the ACMG/AMP framework.