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@article{Helms:2020:10.1161/circgen.120.002929,
author = {Helms, AS and Thompson, AD and Glazier, AA and Hafeez, N and Kabani, S and Rodriguez, J and Yob, JM and Woolcock, H and Mazzarotto, F and Lakdawala, NK and Wittekind, SG and Pereira, AC and Jacoby, DL and Colan, SD and Ashley, EA and Saberi, S and Ware, JS and Ingles, J and Semsarian, C and Michels, M and Olivotto, I and Ho, CY and Day, SM},
doi = {10.1161/circgen.120.002929},
journal = {Circulation: Genomic and Precision Medicine},
pages = {396--405},
title = {Spatial and functional distribution of            MYBPC3            pathogenic variants and clinical outcomes in patients with hypertrophic cardiomyopathy},
url = {http://dx.doi.org/10.1161/circgen.120.002929},
volume = {13},
year = {2020}
}

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TY  - JOUR
AB  - Background - Pathogenic variants in MYBPC3, encoding cardiac MyBP-C, are the most common cause of familial hypertrophic cardiomyopathy. A large number of unique MYBPC3 variants and relatively small genotyped HCM cohorts have precluded detailed genotype-phenotype correlations.Methods - Patients with HCM and MYBPC3 variants were identified from the Sarcomeric Human Cardiomyopathy Registry (SHaRe). Variant types and locations were analyzed, morphologic severity was assessed, and time-event analysis was performed (composite clinical outcome of sudden death, class III/IV heart failure, LVAD/transplant, atrial fibrillation). For selected missense variants falling in enriched domains, myofilament localization and degradation rates were measured in vitro.Results - Among 4,756 genotyped HCM patients in SHaRe, 1,316 patients were identified with adjudicated pathogenic truncating (N=234 unique variants, 1047 patients) or non-truncating (N=22 unique variants, 191 patients) variants in MYBPC3. Truncating variants were evenly dispersed throughout the gene, and hypertrophy severity and outcomes were not associated with variant location (grouped by 5' - 3' quartiles or by founder variant subgroup). Non-truncating pathogenic variants clustered in the C3, C6, and C10 domains (18 of 22, 82%, p<0.001 vs. gnomAD common variants) and were associated with similar hypertrophy severity and adverse event rates as observed with truncating variants. MyBP-C with variants in the C3, C6, and C10 domains was expressed in rat ventricular myocytes. C10 mutant MyBP-C failed to incorporate into myofilaments and degradation rates were accelerated by ~90%, while C3 and C6 mutant MyBP-C incorporated normally with degradation rate similar to wild-type.Conclusions - Truncating variants account for 91% of MYBPC3 pathogenic variants and cause similar clinical severity and outcomes regardless of location, consistent with locus-independent loss-of-function. Non-truncating MYBPC3 pathogenic variants are regi
AU  - Helms,AS
AU  - Thompson,AD
AU  - Glazier,AA
AU  - Hafeez,N
AU  - Kabani,S
AU  - Rodriguez,J
AU  - Yob,JM
AU  - Woolcock,H
AU  - Mazzarotto,F
AU  - Lakdawala,NK
AU  - Wittekind,SG
AU  - Pereira,AC
AU  - Jacoby,DL
AU  - Colan,SD
AU  - Ashley,EA
AU  - Saberi,S
AU  - Ware,JS
AU  - Ingles,J
AU  - Semsarian,C
AU  - Michels,M
AU  - Olivotto,I
AU  - Ho,CY
AU  - Day,SM
DO  - 10.1161/circgen.120.002929
EP  - 405
PY  - 2020///
SN  - 2574-8300
SP  - 396
TI  - Spatial and functional distribution of            MYBPC3            pathogenic variants and clinical outcomes in patients with hypertrophic cardiomyopathy
T2  - Circulation: Genomic and Precision Medicine
UR  - http://dx.doi.org/10.1161/circgen.120.002929
UR  - https://www.ahajournals.org/doi/10.1161/CIRCGEN.120.002929
UR  - http://hdl.handle.net/10044/1/82451
VL  - 13
ER  -

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