👤 S Mital

Variants with large effect contribute to congenital heart disease (CHD). To date, recessive genotypes (RGs) have commonly been implicated through anecdotal ascertainment of consanguineous families and candidate gene-based analysis; the recessive contribution to the broad range of CHD phenotypes has been limited. We analyzed whole exome sequences of 5,424 CHD probands. Rare damaging RGs were estimated to contribute to at least 2.2% of CHD, with greater enrichment among laterality phenotypes (5.4%) versus other subsets (1.4%). Among 108 curated human recessive CHD genes, there were 66 RGs, with 54 in 11 genes with >1 RG, 12 genes with 1 RG, and 85 genes with zero. RGs were more prevalent among offspring of consanguineous union (4.7%, 32/675) than among nonconsanguineous probands (0.7%, 34/4749). Founder variants in Show less

Pathogenic variants in MYH7 and MYBPC3 account for the majority of hypertrophic cardiomyopathy (HCM). Targeted drugs like myosin ATPase inhibitors have not been evaluated in children. We generate patient and variant-corrected iPSC-cardiomyocytes (CMs) from pediatric HCM patients harboring single variants in MYH7 (V606M; R453C), MYBPC3 (G148R) or digenic variants (MYBPC3 P955fs, TNNI3 A157V). We also generate CMs harboring MYBPC3 mono- and biallelic variants using CRISPR editing of a healthy control. Compared with isogenic and healthy controls, variant-positive CMs show sarcomere disorganization, higher contractility, calcium transients, and ATPase activity. However, only MYH7 and biallelic MYBPC3 variant-positive CMs show stronger myosin-actin binding. Targeted myosin ATPase inhibitors show complete rescue of the phenotype in variant-positive CMs and in cardiac Biowires to mirror isogenic controls. The response is superior to verapamil or metoprolol. Myosin inhibitors can be effective in genotypically diverse HCM highlighting the need for myosin inhibitor drug trials in pediatric HCM. Show less

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy. It follows an autosomal dominant inheritance pattern in most cases, with incomplete penetrance and heterogeneity. It is familial in 60% of cases and most of these are caused by pathogenic variants in the core sarcomeric genes ( Show less

Induced pluripotent stem cells (iPSC) derived from healthy individuals are important controls for disease-modeling studies. Here we apply precision health to create a high-quality resource of control iPSCs. Footprint-free lines were reprogrammed from four volunteers of the Personal Genome Project Canada (PGPC). Multilineage-directed differentiation efficiently produced functional cortical neurons, cardiomyocytes and hepatocytes. Pilot users demonstrated versatility by generating kidney organoids, T lymphocytes, and sensory neurons. A frameshift knockout was introduced into MYBPC3 and these cardiomyocytes exhibited the expected hypertrophic phenotype. Whole-genome sequencing-based annotation of PGPC lines revealed on average 20 coding variants. Importantly, nearly all annotated PGPC and HipSci lines harbored at least one pre-existing or acquired variant with cardiac, neurological, or other disease associations. Overall, PGPC lines were efficiently differentiated by multiple users into cells from six tissues for disease modeling, and variant-preferred healthy control lines were identified for specific disease settings. Show less

Current guidelines recommend initiating family screening for hypertrophic cardiomyopathy (HCM) after age 10 or 12 years unless early screening criteria are met. The aim was to evaluate if current screening guidelines miss early onset disease. Children who underwent family screening for HCM before age 18 years were analysed. Major cardiac events (MaCEs) were defined as death, sudden cardiac death (SCD), or need for major cardiac interventions (myectomy, implantable cardioverter-defibrillator insertion, transplantation). Of 524 children screened, 331 were under 10 years of age, 9.9% had echocardiographic evidence of HCM, and 1.1% were symptomatic at first screening. The median (interquartile range) age at HCM onset was 8.9 (4.7-13.4) years, and at MaCE was 10.9 (8.5-14.3) years with a median time to MaCE from HCM onset of 1.5 (0.5-4.1) years. About 52.5% phenotype-positive children and 41% with MaCEs were <10 years old. Only 69% children with early HCM met early screening criteria. Cox regression identified male gender, family history of SCD, and pathogenic variants in MYH7/MYBPC3 as a predictor of early onset HCM and MaCEs. A third of children not eligible for early screening by current guidelines had phenotype-positive HCM. MYH7 and MYBC3 mutation-positive patients were at highest risk for developing early HCM and experiencing an event or requiring a major intervention. Our findings suggest that younger family members should be considered for early clinical and genetic screening to identify the subset in need of closer monitoring and interventions. Show less

Children with hypertrophic cardiomyopathy (HCM) experience sudden cardiac death (SCD) and other life-threatening events. We assessed if affected gene and variant burden predict outcomes. Patients <18 years old with primary HCM with a pathogenic variant or variant of uncertain significance in cardiomyopathy genes were included. Association of gene and variant number and type with freedom from major adverse cardiac events (MACE), that is, ICD insertion, myectomy, aborted SCD, transplantation or death, was assessed by Cox regression. A total of 98 of 155 gene-tested patients carried a non-benign variant. The primary affected gene was MYH7 in 35% (MYH7+) and MYBPC3 in 49% (MYBPC3+). MYH7+ patients had earlier disease onset and higher risk of MACE (hazard ratio 2.7, 95% CI 1.3-5.7). Risk of MACE was also higher in patients with multiple variants (n = 16) (HR 2.5, CI: 1.1-5.9) compared to a propensity score-matched single variant subset, after adjustment for primary gene, and in patients with de novo (n = 18) vs inherited variants (HR 5.7, CI: 2.6-12.7). Affected gene (eg, MYH7), higher variant burden and de novo variant status are independently associated with earlier onset and higher frequency of adverse outcomes in pediatric HCM, highlighting the importance of genetic risk stratification in HCM. Show less