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@article{Mazzarotto:2020:10.1161/CIRCULATIONAHA.119.037661,
author = {Mazzarotto, F and Tayal, U and Buchan, RJ and Midwinter, W and Wilk, A and Whiffin, N and Govind, R and Mazaika, E and de, Marvao A and Dawes, TJW and Felkin, LE and Ahmad, M and Theotokis, PI and Edwards, E and Ing, AY and Thomson, KL and Chan, LLH and Sim, D and Baksi, AJ and Pantazis, A and Roberts, AM and Watkins, H and Funke, B and O'Regan, DP and Olivotto, I and Barton, PJR and Prasad, SK and Cook, SA and Ware, JS and Walsh, R},
doi = {10.1161/CIRCULATIONAHA.119.037661},
journal = {Circulation},
pages = {387--398},
title = {Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.},
url = {http://dx.doi.org/10.1161/CIRCULATIONAHA.119.037661},
volume = {141},
year = {2020}
}

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TY  - JOUR
AB  - BACKGROUND: Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60 706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM. METHODS: We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis. RESULTS: Truncating variants in TTN and DSP were associated with DCM in all comparisons. Variants in MYH7, LMNA, BAG3, TNNT2, TNNC1, PLN, ACTC1, NEXN, TPM1, and VCL were significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to early-onset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal. CONCLUSIONS: In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating in
AU  - Mazzarotto,F
AU  - Tayal,U
AU  - Buchan,RJ
AU  - Midwinter,W
AU  - Wilk,A
AU  - Whiffin,N
AU  - Govind,R
AU  - Mazaika,E
AU  - de,Marvao A
AU  - Dawes,TJW
AU  - Felkin,LE
AU  - Ahmad,M
AU  - Theotokis,PI
AU  - Edwards,E
AU  - Ing,AY
AU  - Thomson,KL
AU  - Chan,LLH
AU  - Sim,D
AU  - Baksi,AJ
AU  - Pantazis,A
AU  - Roberts,AM
AU  - Watkins,H
AU  - Funke,B
AU  - O'Regan,DP
AU  - Olivotto,I
AU  - Barton,PJR
AU  - Prasad,SK
AU  - Cook,SA
AU  - Ware,JS
AU  - Walsh,R
DO  - 10.1161/CIRCULATIONAHA.119.037661
EP  - 398
PY  - 2020///
SP  - 387
TI  - Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.
T2  - Circulation
UR  - http://dx.doi.org/10.1161/CIRCULATIONAHA.119.037661
UR  - https://www.ncbi.nlm.nih.gov/pubmed/31983221
UR  - http://hdl.handle.net/10044/1/75254
VL  - 141
ER  -

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Dr Francesco Mazzarotto

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