%0 Journal Article %J NPJ Genom Med %D 2022 %T Whole genome sequencing delineates regulatory, copy number, and cryptic splice variants in early onset cardiomyopathy. %A Lesurf, Robert %A Said, Abdelrahman %A Akinrinade, Oyediran %A Breckpot, Jeroen %A Delfosse, Kathleen %A Liu, Ting %A Yao, Roderick %A Persad, Gabrielle %A McKenna, Fintan %A Noche, Ramil R %A Oliveros, Winona %A Mattioli, Kaia %A Shah, Shreya %A Miron, Anastasia %A Yang, Qian %A Meng, Guoliang %A Yue, Michelle Chan Seng %A Sung, Wilson W L %A Thiruvahindrapuram, Bhooma %A Lougheed, Jane %A Oechslin, Erwin %A Mondal, Tapas %A Bergin, Lynn %A Smythe, John %A Jayappa, Shashank %A Rao, Vinay J %A Shenthar, Jayaprakash %A Dhandapany, Perundurai S %A Semsarian, Christopher %A Weintraub, Robert G %A Bagnall, Richard D %A Ingles, Jodie %A Melé, Marta %A Maass, Philipp G %A Ellis, James %A Scherer, Stephen W %A Mital, Seema %X

Cardiomyopathy (CMP) is a heritable disorder. Over 50% of cases are gene-elusive on clinical gene panel testing. The contribution of variants in non-coding DNA elements that result in cryptic splicing and regulate gene expression has not been explored. We analyzed whole-genome sequencing (WGS) data in a discovery cohort of 209 pediatric CMP patients and 1953 independent replication genomes and exomes. We searched for protein-coding variants, and non-coding variants predicted to affect the function or expression of genes. Thirty-nine percent of cases harbored pathogenic coding variants in known CMP genes, and 5% harbored high-risk loss-of-function (LoF) variants in additional candidate CMP genes. Fifteen percent harbored high-risk regulatory variants in promoters and enhancers of CMP genes (odds ratio 2.25, p = 6.70 × 10 versus controls). Genes involved in α-dystroglycan glycosylation (FKTN, DTNA) and desmosomal signaling (DSC2, DSG2) were most highly enriched for regulatory variants (odds ratio 6.7-58.1). Functional effects were confirmed in patient myocardium and reporter assays in human cardiomyocytes, and in zebrafish CRISPR knockouts. We provide strong evidence for the genomic contribution of functionally active variants in new genes and in regulatory elements of known CMP genes to early onset CMP.

%B NPJ Genom Med %V 7 %P 18 %8 2022 Mar 14 %G eng %N 1 %R 10.1038/s41525-022-00288-y %0 Journal Article %J J Med Genet %D 2021 %T Ribosomal protein S6 kinase beta-1 gene variants cause hypertrophic cardiomyopathy. %A Jain, Pratul Kumar %A Jayappa, Shashank %A Sairam, Thiagarajan %A Mittal, Anupam %A Paul, Sayan %A Rao, Vinay J %A Chittora, Harshil %A Kashyap, Deepak K %A Palakodeti, Dasaradhi %A Thangaraj, Kumarasamy %A Shenthar, Jayaprakash %A Koranchery, Rakesh %A Rajendran, Ranjith %A Alireza, Haghighi %A Mohanan, Kurukkanparampil Sreedharan %A Rathinavel, Andiappan %A Dhandapany, Perundurai S %X

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease with preserved or increased ejection fraction in the absence of secondary causes. Mutations in the sarcomeric protein-encoding genes predominantly cause HCM. However, relatively little is known about the genetic impact of signalling proteins on HCM.

METHODS AND RESULTS: Here, using exome and targeted sequencing methods, we analysed two independent cohorts comprising 401 Indian patients with HCM and 3521 Indian controls. We identified novel variants in ribosomal protein S6 kinase beta-1 () gene in two unrelated Indian families as a potential candidate gene for HCM. The two unrelated HCM families had the same heterozygous missense S6K1 variant (p.G47W). In a replication association study, we identified two S6K1 heterozygotes variants (p.Q49K and p.Y62H) in the UK Biobank cardiomyopathy cohort (n=190) compared with matched controls (n=16 479). These variants are neither detected in region-specific controls nor in the human population genome data. Additionally, we observed an S6K1 variant (p.P445S) in an Arab patient with HCM. Functional consequences were evaluated using representative S6K1 mutated proteins compared with wild type in cellular models. The mutated proteins activated the S6K1 and hyperphosphorylated the rpS6 and ERK1/2 signalling cascades, suggesting a gain-of-function effect.

CONCLUSIONS: Our study demonstrates for the first time that the variants in the gene are associated with HCM, and early detection of the variant carriers can help to identify family members at risk and subsequent preventive measures. Further screening in patients with HCM with different ethnic populations will establish the specificity and frequency of gene variants.

%B J Med Genet %8 2021 Dec 16 %G eng %R 10.1136/jmedgenet-2021-107866