Establishing Clinical Validity Classifications for the RASopathies
Brandon Cushman1 and Lisa Vincent2 on behalf of the ClinGen RASopathies Expert Panel
1Laboratory for Molecular Medicine, Partners Healthcare Personalized Medicine, Cambridge, Massachusetts, USA
2GeneDx, Inc., Gaithersburg, Maryland, USA
The RASopathies are a group of syndromic disorders caused by dysregulation in the RAS/mitogen-activated protein kinase (MAPK) pathway. The disorders include Noonan syndrome (NS), cardiofaciocutaneous syndrome (CFC), Costello syndrome (CS), Noonan syndrome with multiple lentigines (NSML), Noonan-like syndrome, neurofibromatosis type 1 (NF1), and Legius syndrome. RASopathies are estimated to affect 1:1000 newborns1. While phenotypically heterogeneous, the disorders share some overlap in clinical presentation because of their common pathogenic mechanism resulting in dysfunction of the RAS/MAPK signaling pathway. Presentations include craniofacial dysmorphism, developmental delay, and generalized hypotonia, as well as musculoskeletal, ocular, and cutaneous abnormalities2. Each disorder is differentiated based on both its clinical presentation and genetic etiology3.
Established in 2015, the ClinGen RASopathies Expert Panel (RAS EP) strives to establish the clinical validity of the gene-disease associations within the RASopathies and to refine the ACMG classification criteria4 for the interpretation of variants in those genes.
Using the semi-quantitative method for validating gene-disease associations established by the ClinGen Gene Curation Working Group5, the RAS EP preliminarily assessed 11 genes and their association with at least 1 of 5 RASopathies for a total of 25 gene-disease pairs. Of these, 9 genes were assessed for NS, 5 for CFC, 4 for CS, 5 for NSML and 1 for Noonan-like syndrome. As new gene-disease associations are published, the RAS EP aims to curate and assess their association with this group of disorders.