Contemporary Insights Into the Genetics of Hypertrophic Cardiomyopathy: Toward a New Era in Clinical Testing? Journal of the American Heart Association Genetic testing for hypertrophic cardiomyopathy (HCM) is an established clinical technique, supported by 30 years of research into its genetic etiology. Although pathogenic variants are often detected in patients and used to identify at-risk relatives, the effectiveness of genetic testing has been hampered by ambiguous genetic associations (yielding uncertain and potentially false-positive results), difficulties in classifying variants, and uncertainty about genotype-negative patients. Recent case-control studies on rare variation, improved data sharing, and meta-analysis of case cohorts contributed to new insights into the genetic basis of HCM. In particular, although research into new genes and mechanisms remains essential, reassessment of Mendelian genetic associations in HCM argues that current clinical genetic testing should be limited to a small number of validated disease genes that yield informative and interpretable results. Accurate and consistent variant interpretation has benefited from new standardized variant interpretation guidelines and innovative approaches to improve classification. Most cases lacking a pathogenic variant are now believed to indicate non-Mendelian HCM, with more benign prognosis and minimal risk to relatives. Here, we discuss recent advances in the genetics of HCM and their application to clinical genetic testing together with practical issues regarding implementation. Although this review focuses on HCM, many of the issues discussed are also relevant to other inherited cardiac diseases. 10.1161/JAHA.119.015473

Formin Homology 2 Domain Containing 3 (FHOD3) Is a Genetic Basis for Hypertrophic Cardiomyopathy. Ochoa Juan Pablo,Sabater-Molina María,García-Pinilla José Manuel,Mogensen Jens,Restrepo-Córdoba Alejandra,Palomino-Doza Julián,Villacorta Eduardo,Martinez-Moreno Marina,Ramos-Maqueda Javier,Zorio Esther,Peña-Peña Maria L,García-Granja Pablo E,Rodríguez-Palomares José F,Cárdenas-Reyes Ivonne J,de la Torre-Carpente María M,Bautista-Pavés Alicia,Akhtar Mohammed M,Cicerchia Marcos N,Bilbao-Quesada Raquel,Mogollón-Jimenez Maria Victoria,Salazar-Mendiguchía Joel,Mesa Latorre José M,Arnaez Blanca,Olavarri-Miguel Ivan,Fuentes-Cañamero María E,Lamounier Arsonval,Pérez Ruiz José María,Climent-Payá Vicente,Pérez-Sanchez Inmaculada,Trujillo-Quintero Juan P,Lopes Luis R,Repáraz-Andrade Alfredo,Marín-Iglesias Rosario,Rodriguez-Vilela Alejandro,Sandín-Fuentes María,Garrote Jose A,Cortel-Fuster Alejandro,Lopez-Garrido Miguel,Fontalba-Romero Ana,Ripoll-Vera Tomás,Llano-Rivas Isabel,Fernandez-Fernandez Xusto,Isidoro-García María,Garcia-Giustiniani Diego,Barriales-Villa Roberto,Ortiz-Genga Martín,García-Pavía Pablo,Elliott Perry M,Gimeno Juan R,Monserrat Lorenzo Journal of the American College of Cardiology BACKGROUND:The genetic cause of hypertrophic cardiomyopathy remains unexplained in a substantial proportion of cases. Formin homology 2 domain containing 3 (FHOD3) may have a role in the pathogenesis of cardiac hypertrophy but has not been implicated in hypertrophic cardiomyopathy. OBJECTIVES:This study sought to investigate the relation between FHOD3 mutations and the development of hypertrophic cardiomyopathy. METHODS:FHOD3 was sequenced by massive parallel sequencing in 3,189 hypertrophic cardiomyopathy unrelated probands and 2,777 patients with no evidence of cardiomyopathy (disease control subjects). The authors evaluated protein-altering candidate variants in FHOD3 for cosegregation, clinical characteristics, and outcomes. RESULTS:The authors identified 94 candidate variants in 132 probands. The variants' frequencies were significantly higher in patients with hypertrophic cardiomyopathy (74 of 3,189 [2.32%]) than in disease control subjects (18 of 2,777 [0.65%]; p < 0.001) or in the gnomAD database (1,049 of 138,606 [0.76%]; p < 0.001). FHOD3 mutations cosegregated with hypertrophic cardiomyopathy in 17 families, with a combined logarithm of the odds score of 7.92, indicative of very strong segregation. One-half of the disease-causing variants were clustered in a small conserved coiled-coil domain (amino acids 622 to 655); odds ratio for hypertrophic cardiomyopathy was 21.8 versus disease control subjects (95% confidence interval: 1.3 to 37.9; p < 0.001) and 14.1 against gnomAD (95% confidence interval: 6.9 to 28.7; p < 0.001). Hypertrophic cardiomyopathy patients carrying (likely) pathogenic mutations in FHOD3 (n = 70) were diagnosed after age 30 years (mean 46.1 ± 18.7 years), and two-thirds (66%) were males. Of the patients, 82% had asymmetric septal hypertrophy (mean 18.8 ± 5 mm); left ventricular ejection fraction <50% was present in 14% and hypertrabeculation in 16%. Events were rare before age 30 years, with an annual cardiovascular death incidence of 1% during follow-up. CONCLUSIONS:FHOD3 is a novel disease gene in hypertrophic cardiomyopathy, accounting for approximately 1% to 2% of cases. The phenotype and the rate of cardiovascular events are similar to those reported in unselected cohorts. The FHOD3 gene should be routinely included in hypertrophic cardiomyopathy genetic testing panels. 10.1016/j.jacc.2018.10.001