Genomic ascertainment to quantify prevalence and cancer risk in adults with pathogenic and likely pathogenic germline variants in RASopathy genes

PurposeGenomic ascertainment of electronic health record-linked exome data in two large biobanks was used to quantify germline pathogenic/likely pathogenic (P/LP) variant prevalence, cancer prevalence, and survival in adults with non-NF1 RAS/mitogen-activated protein kinase genes (RASopathies). Patients and MethodsGermline RASopathy variants were examined from adult participants in UK Biobank (UKBB; n=469,802), Geisinger MyCode (n=167,050) and Mount Sinai BioMe (n=30,470). Variants were classified as per American College of Medical Genetics/Association for Molecular Pathology criteria and reviewed by a RASopathy variant expert. Heterozygotes harbored a RASopathy pathogenic/likely pathogenic variant; controls harbored wild type or benign/likely benign RASopathy variation. To distinguish germline variants from clonal hematopoiesis, benign tissues were Sanger sequenced. Tumor phenotype and demographic data were retrieved from MyCode and UKBB. ResultsPathogenic variants in Noonan syndrome-associated genes (excluding known Noonan syndrome with multiple lentigines variants) were the most common with an estimated prevalence that ranged between 1:1,772-1:3,330 in the three cohorts. Pathogenic variants in cardiofaciocutaneous syndrome-associated genes had an estimated prevalence of 1:41,762- 1:55,683 in two cohorts. Pathogenic variants in SPRED1 (Legius syndrome) were more frequent in UKBB (1:19,567 [95%CI: 1:13,150-1:29,116]) compared to MyCode (1:41,762 [95%CI: 1:15,185-1:130,367]). In SPRED1-heterozygotes, cancer prevalence was significantly increased in UKBB (OR:3.8 [95% CI: 2.48-8.64]; p=1.2x10-3) but not in the MyCode cohort. Pathogenic variants in HRAS (Costello syndrome) were not identified. In MyCode and UKBB cohorts, there was no significant increase in cancer prevalence in individuals with Noonan-, CBL- and CFC syndrome-associated pathogenic variants. ConclusionGenomic ascertainment from two large biobanks did not show evidence of elevated cancer risk in adult Noonan syndrome heterozygotes. There may be an increased cancer risk for adult SPRED1 heterozygotes.