Open AccessALU transposition induces familial hypertrophic cardiomyopathy
Author(s) -
Nfonsam Landry,
Huang Lijia,
Carson Nancy,
McGowanJordan Jean,
Beaulieu Bergeron Melanie,
Goobie Sharan,
Conacher Susan,
McCarty David,
Benson Lee,
Hewson Stacy,
Zahavich Laura,
SinclairBourque Elizabeth,
Smith Amanda,
Potter Ryan,
Ghani Mahdi,
Bronicki Lucas,
Jarinova Olga
Publication year - 2020
Publication title -
molecular genetics and genomic medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.765
H-Index - 29
ISSN - 2324-9269
DOI - 10.1002/mgg3.951
Subject(s) - haploinsufficiency , hypertrophic cardiomyopathy , cardiomyopathy , medicine , multiplex ligation dependent probe amplification , sanger sequencing , genetics , copy number variation , biology , gene , exon , heart failure , phenotype , mutation , genome
Background Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy (LVH) in the absence of predisposing cardiovascular conditions. Pathogenic variants in at least 16 cardiac sarcomeric genes have been implicated in HCM, most of which act in a dominant‐negative fashion. However loss‐of‐function (haploinsufficiency) is the most common disease mechanism for pathogenic variants in MYBPC3 , suggesting that MYBPC3 complete deletion may play a role in HCM pathogenesis. Here, we investigate MYBPC3 complete deletion as a disease mechanism in HCM by analyzing two unrelated patients with confirmed diagnosis of HCM that tested negative by Sanger sequencing analysis. Methods MYBPC3 complete deletion was investigated by Multiplex ligation‐dependent probe amplification (MLPA) and microarray analyses. The mechanism of deletion was investigated by interrogating the SINEBase database. Results Patient‐1 was diagnosed with nonobstructive HCM in his mid‐40s while undergoing assessment for palpitations, and patient‐2 with obstructive HCM in his late‐20s while undergoing systolic heart murmur assessment for an unrelated illness. MLPA testing revealed a heterozygous deletion of all MYBPC3 exons in both patients. Subsequent microarray testing confirmed these deletions which extended beyond the 5′ and 3′ ends of MYBPC3 . Genomic assessment suggested that these deletions resulted from Alu/Alu ‐homologous recombination. Conclusion Our results demonstrate that haploinsufficiency resulting from MYBPC3 complete deletion, potentially mediated by Alu recombination, is an important disease mechanism in cardiomyopathy and emphasizes the importance of copy number variation analysis in patients clinically suspected of HCM.