Cardiomyopathy is the leading cause of sudden death in young people, and an important cause of heart failure at any age. Hypertrophic cardiomyopathy (HCM) is typically associated with autosomal dominant mutations in genes encoding proteins of the sarcomere. Dilated cardiomyopathy (DCM), also results from mutations in some of the same sarcomeric proteins but leads to ventricular chamber dilation and reduced systolic performance, rather than hypertrophy.
Despite technological advances in genetic testing, a definitive molecular diagnosis is obtained for only 50% of patients. We therefore need to understand more about the genetic determinants underpinning cardiomyopathy, which will expand our knowledge of the underlying disease mechanisms and lead to possible new therapeutic approaches.
In our paper out this month we show using genome-wide linkage analysis and exome sequencing that homozygous mutations in KLHL24 cause HCM in two consanguineous families. Of the eleven young affected adults in our study, three died suddenly and one had a cardiac transplant due to heart failure, highlighting the severity of this form of HCM. We also show that knock-down of the gene in zebrafish results in heart defects providing additional support for KLHL24 as a HCM-associated gene.
Hedberg-Oldfors C, Abramsson A, Osborn DPS, Danielsson O, Fazlinezhad A, Nilipour Y, Hübbert L, Nennesmo I, Visuttijai K, Bharj J, Petropoulou E, Shoreim A, Vona B, Ahangari N, López MD, Doosti M, Banote RK, Maroofian R, Edling M, Taherpour M, Zetterberg Md H, Karimiani EG, Oldfors A, Jamshidi Y.
Hum Mol Genet. 2019 Feb 1.