Prevalence of pathogenic and likely pathogenic variants in the RASopathy genes in patients who have had panel testing for cardiomyopathy

Abstract

RASopathies are a group of developmental disorders caused by pathogenic variants in the RAS-MAPK pathway. Cardiomyopathy is a major feature of this group of disorders, specifically hypertrophic cardiomyopathy (HCM). HCM can be the first presenting feature in individuals with RASopathies. We conducted a retrospective study of all individuals who have had a cardiomyopathy gene panel ordered through our institution to determine the prevalence of pathogenic or likely pathogenic variants in RAS pathway genes in individuals with cardiomyopathy.We evaluated variants in the following genes: BRAF, CBL, HRAS, KRAS, MAP2K1, MAP2K2, NF1, NRAS, PTPN11, RAF1, SHOC2, and SOS1. We reviewed 74 cases with cardiomyopathy, including 32 with HCM, 24 with dilated cardiomyopathy (DCM), nine with both left ventricular noncompaction (LVNC) and DCM, four with LVNC only, two with arrhythmogenic right ventricular cardiomyopathy (ARVC) and three with unspecified cardiomyopathy. We identified four patients (5.41%) with pathogenic or likely pathogenic variants in HRAS, PTPN11 and RAF1 (two individuals). Indication for testing for all four individuals was HCM. The prevalence of pathogenic or likely pathogenic variants in RASopathy genes in our HCM patient cohort is 12.5% (4/32). We conclude that the RASopathy genes should be included on multi-gene panels for cardiomyopathy to increase diagnostic yield for individuals with HCM.

High-Resolution Cryo-EM Structure of the Cardiac Actomyosin Complex

“…Therefore, we hypothesize that Y218H/S and D222Y may alter the positioning of the following short 224-230 helix of actin and affect the inter-subdomain contacts within the actin molecule. T229 (T229R) (Yoshida et al, 2016) and A230 (A230T/V) (Aljeaid et al, 2019;Van Driest et al, 2003) structure the short 224-230 helix of actin. The following I250 (I250M/T) (Dal Ferro et al, 2017;Lakdawala et al, 2012) makes a hydrophobic interaction with L193 of the 182-193 helix (Figure 4D, yellow arrow), so that it interconnects both elements of SD4 involved in direct interactions between actin protomers.…”

Diagnostic yield of genetic testing in a heterogeneous cohort of 1376 HCM patients

“…Patients underwent testing as ordered by their healthcare provider for either an HCM panel (16,19 25) NGS method on the NextSeq sequencing system (Illumina). The remaining patients (17.7%) were analyzed using an in-house tailored Integrated DNA Technologies (IDT) based whole exome sequencing platform run on the NovaSeq sequencing system (Illumina).…”

“…Recent work by the HCM ClinGen Gene Curation Expert Panel determined that only 46% of evaluated HCM/intrinsic cardiomyopathy and syndromic genes associated with isolated left ventricular hypertrophy (LVH) routinely included on testing panels were categorized as having a definite, strong or moderate association with the disease [18]. Among these are three RASopathy genes (RAF1, RIT1 and PTPN11), which have been shown to cause isolated LVH in some patients, but have only been comprehensively evaluated in a small number of studies [19,20]. An absence of syndromic features in some patients could be explained by mild syndromic gestalt and/or low to intermediate level mosaicism, which may not be detected by certain NGS platforms without sufficient read depth.…”

Metalloproteinases and Hypertrophic Cardiomyopathy: A Systematic Review

“…Clinical signs and symptoms of HCM can range from asymptomatic disorders to progressive cardiac failure [ 2 ]. HCM is also a substantial factor in sudden cardiac mortality in young people, even well-trained athletes, equally affecting both sexes and regardless of race [ 3 , 4 , 5 ]. A common finding in HCM patients is left ventricular outflow obstruction brought on by asymmetric septal hypertrophy.…”

“…The left ventricular outflow tract is frequently obstructed as a result. Septal hypertrophy is caused by genetic flaws in a number of different genes [ 1 , 3 , 4 , 5 ].…”