Abstract
Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death. Mutations in the MYBPC3 gene represent the cause of HCM in ~35% of patients with HCM. However, genetic testing in clinic setting has been limited due to the cost and relatively time-consuming by Sanger sequencing. Here, we developed a HCM Molecular Diagnostic Kit enabling ultra-low-cost targeted gene resequencing in a large cohort and investigated the mutation spectrum of MYBPC3. In a cohort of 114 patients with HCM, a total of 20 different mutations (8 novel and 12 known mutations) of MYBPC3 were identified from 25 patients (21.9%). We demonstrated that the power of targeted resequencing in a cohort of HCM patients, and found that MYBPC3 is a common HCM-causing gene in Chinese patients. Phenotype-genotype analyses showed that the patients with double mutations (n = 2) or premature termination codon mutations (n = 12) showed more severe manifestations, compared with patients with missense mutations (n = 11). Particularly, we identified a recurrent truncation mutation (p.Y842X) in four unrelated cases (4/25, 16%), who showed severe phenotypes, and suggest that the p.Y842X is a frequent mutation in Chinese HCM patients with severe phenotypes.
Highlights
Hypertrophic cardiomyopathy (HCM) is a major cause of sudden cardiac death
Genetic testing is routinely recommended in patients with HCM according to current clinical guidelines[3,7], but its use at clinic has been limited by the cost and time-consuming conventional sequencing technologies
Our results have shown that the patients with double mutations (n = 2 ) or premature stop codon (PTC) mutations (n = 1 2) are correlated with more severe manifestations requiring invasive therapies, compared with patients with missense mutations (n = 11) (p = 0.01)
Summary
By filtering multiple databases (dbSNP137, HapMap, 1000 Genome, ESP6500, and 300 Chinese Han exome in-house database), we identified 8 novel mutations (2 missense, 1 nonsense, and 5 InDel-induced frameshift mutations) as well as 12 known causative mutations (as shown in the HGMD database) All of these 20 mutations were predicted to be probably pathogenic by SIFT and Polyphen-2, and further confirmed by Sanger sequencing analyses (the forward sequencing data are shown in Fig. 2b; the reverse sequencing results are included in Supplementary Fig. S2 online). Its combination with p.R160W in the patient R0248 may have led to the onset of the disease at younger age, severe clinical symptoms as well as severe hypertrophy for receiving septum myectomy It was not determined whether these double mutations were compound mutations or occurred in the same allele (cis). No correlation was found between other clinical indications and missense mutation group, PTC group and double mutations group
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
