Imperial College London
Alternate

ProfessorStuartCook

Faculty of Medicine, Institute of Clinical Sciences

Visiting Professor
 
 
 
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Contact

 

+44 (0)20 3313 1346stuart.cook

 
 
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Location

 

RF 16Sydney StreetRoyal Brompton Campus

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Summary

 

Publications

Citation

BibTex format

@article{McGurk:2023:10.1016/j.ajhg.2023.08.003,
author = {McGurk, K and Zhang, X and Theotokis, P and Thomson, K and Harper, A and Buchan, R and Mazaika, E and Ormondroyd, E and Wright, W and Macaya, D and Chee, Jian P and Funke, B and MacArthur, D and Prasad, S and Cook, S and Allouba, M and Aguib, Y and Yacoub, M and O'Regan, D and Barton, P and Watkins, H and Bottolo, L and Ware, J},
doi = {10.1016/j.ajhg.2023.08.003},
journal = {American Journal of Human Genetics},
pages = {1482--1495},
title = {The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings},
url = {http://dx.doi.org/10.1016/j.ajhg.2023.08.003},
volume = {110},
year = {2023}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.
AU  - McGurk,K
AU  - Zhang,X
AU  - Theotokis,P
AU  - Thomson,K
AU  - Harper,A
AU  - Buchan,R
AU  - Mazaika,E
AU  - Ormondroyd,E
AU  - Wright,W
AU  - Macaya,D
AU  - Chee,Jian P
AU  - Funke,B
AU  - MacArthur,D
AU  - Prasad,S
AU  - Cook,S
AU  - Allouba,M
AU  - Aguib,Y
AU  - Yacoub,M
AU  - O'Regan,D
AU  - Barton,P
AU  - Watkins,H
AU  - Bottolo,L
AU  - Ware,J
DO  - 10.1016/j.ajhg.2023.08.003
EP  - 1495
PY  - 2023///
SN  - 0002-9297
SP  - 1482
TI  - The penetrance of rare variants in cardiomyopathy-associated genes: a cross-sectional approach to estimate penetrance for secondary findings
T2  - American Journal of Human Genetics
UR  - http://dx.doi.org/10.1016/j.ajhg.2023.08.003
UR  - https://www.sciencedirect.com/science/article/pii/S0002929723002793
UR  - http://hdl.handle.net/10044/1/105824
VL  - 110
ER  -
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