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@article{Walsh:2017:eurheartj/ehw603,
author = {Walsh, R and Buchan, R and Wilk, A and John, S and Felkin, L and Thomson, KL and Chiaw, TH and Chin, Woon Loong C and Jian, Pua C and Raphael, C and Prasad, S and Barton, P and Funke, B and Watkins, H and Ware, J and Cook, SA},
doi = {eurheartj/ehw603},
journal = {European Heart Journal},
pages = {3461--3468},
title = {Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes},
url = {http://dx.doi.org/10.1093/eurheartj/ehw603},
volume = {38},
year = {2017}
}

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TY  - JOUR
AB  - Aim: Hypertrophic cardiomyopathy (HCM)exhibits genetic heterogeneity that is dominated by variation in eight sarcomericgenes.Genetic variation in a large number of non-sarcomeric genes has also been implicated in HCM but not formally assessed. Here we used very large case and control cohorts to determine the extent to which variation in non-sarcomeric genes contributes to HCM.Methods and results: We sequenced known and putative HCM genes ina new large prospective HCM cohort (n=804) and analysed data alongside the largest published series of clinically genotyped HCM patients (n=6179), previously published HCM cohorts and reference population samples from the Exome Aggregation Consortium (ExAC, n=60,706) to assess variation in 31 genes implicated in HCM. We foundno significant excess of rare (minor allele frequency < 1:10,000 in ExAC)protein-alteringvariants over controls for most genes tested and conclude that novel variantsin these genes are rarely interpretable, even for genes with previous evidence of co-segregation (e.g. ACTN2). To provide an aid for variant interpretation, weintegratedHCM gene sequencedata with aggregatedpedigreeand functional data and suggest ameans of assessing genepathogenicity in HCMusing this evidence. Conclusions: We show that genetic variation in the majority of non-sarcomeric genes implicated in HCM is not associated with the condition, reinforce the fact that the sarcomeric gene variation is the primary cause of HCM known to date and underscore that the aetiology of HCM is unknown in the majority ofpatients.
AU  - Walsh,R
AU  - Buchan,R
AU  - Wilk,A
AU  - John,S
AU  - Felkin,L
AU  - Thomson,KL
AU  - Chiaw,TH
AU  - Chin,Woon Loong C
AU  - Jian,Pua C
AU  - Raphael,C
AU  - Prasad,S
AU  - Barton,P
AU  - Funke,B
AU  - Watkins,H
AU  - Ware,J
AU  - Cook,SA
DO  - eurheartj/ehw603
EP  - 3468
PY  - 2017///
SN  - 1522-9645
SP  - 3461
TI  - Defining the genetic architecture of hypertrophic cardiomyopathy: re-evaluating the role of non-sarcomeric genes
T2  - European Heart Journal
UR  - http://dx.doi.org/10.1093/eurheartj/ehw603
UR  - http://hdl.handle.net/10044/1/42794
VL  - 38
ER  -

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