Assessing the Gene-Disease Association of 19 Genes with the RASopathies using the ClinGen Gene Curation Framework

Abstract

AbstractThe RASopathies are a complex group of diseases regarding phenotype and genetic etiology. The ClinGen RASopathy Expert Panel assessed published and other publicly available evidence supporting the association of 19 genes with RASopathy conditions. Using the semi-quantitative literature curation method developed by the ClinGen Gene Curation Working Group, evidence for each gene was curated and scored for Noonan syndrome, Costello syndrome, cardiofaciocutaneous (CFC) syndrome, Noonan syndrome with multiple lentigines (NSML), and Noonan-like syndrome with loose anagen hair (NS/LAH).The curated evidence supporting each gene-disease relationship was then discussed and approved by the ClinGen RASopathy Expert Panel. Each association’s strength was classified as Definitive, Strong, Moderate, Limited, Disputed, or No Evidence. Eleven genes were classified as definitively associated with at least one RASopathy condition. Two genes classified as strong for association with at least one RASopathy condition while one gene was moderate and three were limited. The RAS EP also refuted the association of two genes for a RASopathy condition. Overall, our results provide a greater understanding of the different gene-disease relationships within the RASopathies and can help guide and direct clinicians, patients and researchers who are identifying variants in individuals with a suspected RASopathyGRANT NUMBERS:Research reported in this publication was supported by the National Human Genome Research Institute (NHGRI) under award number U41HG006834. MZ received support from German Federal Ministry of Education and Research (BMBF): NSEuroNet (FKZ 01GM1602A), GeNeRARe (FKZ 01GM1519A).