Genetic pleiotropy of ERCC6 loss-of-function and deleterious missense variants links retinal dystrophy, arrhythmia, and immunodeficiency in diverse ancestries.

Arrhythmias, Cardiac DNA Helicases DNA Repair Enzymes Exome Genetic Pleiotropy Humans Poly-ADP-Ribose Binding Proteins Retinal Dystrophies / genetics Exome Sequencing / methods
ERCC6 genotype-first diagnosis pleiotropy rare variant whole-exome sequencing

Journal

Human mutation
ISSN: 1098-1004
Titre abrégé: Hum Mutat
Pays: United States
ID NLM: 9215429

Informations de publication

Date de publication:
08 2021
Historique:
revised: 27 04 2021
received: 16 11 2020
accepted: 15 05 2021
pubmed: 19 5 2021
medline: 1 4 2022
entrez: 18 5 2021
Statut: ppublish

Résumé

Biobanks with exomes linked to electronic health records (EHRs) enable the study of genetic pleiotropy between rare variants and seemingly disparate diseases. We performed robust clinical phenotyping of rare, putatively deleterious variants (loss-of-function [LoF] and deleterious missense variants) in ERCC6, a gene implicated in inherited retinal disease. We analyzed 213,084 exomes, along with a targeted set of retinal, cardiac, and immune phenotypes from two large-scale EHR-linked biobanks. In the primary analysis, a burden of deleterious variants in ERCC6 was strongly associated with (1) retinal disorders; (2) cardiac and electrocardiogram perturbations; and (3) immunodeficiency and decreased immunoglobulin levels. Meta-analysis of results from the BioMe Biobank and UK Biobank showed a significant association of deleterious ERCC6 burden with retinal dystrophy (odds ratio [OR] = 2.6, 95% confidence interval [CI]: 1.5-4.6; p = 8.7 × 10

Identifiants

DOI: 10.1002/humu.24220 PMID: 34005834 PMC: PMC8295228
pubmed: 34005834
doi: 10.1002/humu.24220
pmc: PMC8295228
mid: NIHMS1706664
doi:

Substances chimiques

Poly-ADP-Ribose Binding Proteins 0
DNA Helicases EC 3.6.4.-
ERCC6 protein, human EC 3.6.4.12
DNA Repair Enzymes EC 6.5.1.-

Types de publication

Journal Article Meta-Analysis Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

969-977

Subventions

Organisme : Medical Research Council
ID : MC_PC_17228
Pays : United Kingdom
Organisme : NIGMS NIH HHS
ID : R35 GM124836
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL139865
Pays : United States
Organisme : NEI NIH HHS
ID : R01 EY015473
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM007280
Pays : United States
Organisme : NHLBI NIH HHS
ID : R01 HL155915
Pays : United States
Organisme : Medical Research Council
ID : MC_QA137853
Pays : United Kingdom
Organisme : NIH HHS
ID : S10 OD018522
Pays : United States
Organisme : NIH HHS
ID : S10 OD026880
Pays : United States

Informations de copyright

© 2021 Wiley Periodicals LLC.

Références

Genet Med. 2007 Mar;9(3):141-9
pubmed: 17413418
Eye (Lond). 1998;12 ( Pt 3b):571-9
pubmed: 9775219
Genome Biol. 2016 Jun 06;17(1):122
pubmed: 27268795
Mol Vis. 2016 Aug 29;22:1062-76
pubmed: 27625572
DNA Repair (Amst). 2012 May 1;11(5):488-501
pubmed: 22483866
PLoS One. 2013 Jun 14;8(6):e65574
pubmed: 23940504
Nucleic Acids Res. 2019 Jan 8;47(D1):D886-D894
pubmed: 30371827
Nature. 2018 Oct;562(7726):203-209
pubmed: 30305743
Am J Hum Genet. 2014 Jul 3;95(1):5-23
pubmed: 24995866
Graefes Arch Clin Exp Ophthalmol. 2008 Apr;246(4):491-9
pubmed: 17917739
Am J Hum Genet. 2018 Jul 5;103(1):58-73
pubmed: 29961570
Genet Med. 2020 Jan;22(1):102-111
pubmed: 31383942
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4
pubmed: 12824425
Nat Commun. 2020 Jan 28;11(1):542
pubmed: 31992710
Genome Biol. 2009;10(11):R130
pubmed: 19919682
Nat Rev Genet. 2011 Jun;12(6):417-28
pubmed: 21587298
Database (Oxford). 2016 Apr 05;2016:
pubmed: 27048349
Am J Hum Genet. 2003 Dec;73(6):1217-39
pubmed: 14639525
Nature. 2014 Feb 13;506(7487):185-90
pubmed: 24463508
Nat Methods. 2010 Aug;7(8):575-6
pubmed: 20676075
Genet Med. 2016 May;18(5):483-93
pubmed: 26204423
Science. 2016 Dec 23;354(6319):
pubmed: 28008009
Front Genet. 2014 Jun 19;5:187
pubmed: 24995013
Nat Genet. 2013 Jun;45(6):580-5
pubmed: 23715323
Am J Med Genet. 1992 Jan 1;42(1):68-84
pubmed: 1308368
Nature. 2015 Feb 5;518(7537):102-6
pubmed: 25487149
Cell Rep. 2020 Jan 14;30(2):465-480.e6
pubmed: 31940490
Nat Genet. 2021 Jul;53(7):942-948
pubmed: 34183854
Nature. 2020 Oct;586(7831):749-756
pubmed: 33087929
Curr Protoc Hum Genet. 2013 Jan;Chapter 7:Unit7.20
pubmed: 23315928
Arch Ophthalmol. 2005 Mar;123(3):321-7
pubmed: 15767473

Auteurs

Iain S Forrest (IS)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Medical Scientist Training Program, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
ORCID: 0000-0002-5642-422X

Kumardeep Chaudhary (K)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Ha My T Vy (HMT)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Shantanu Bafna (S)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Soyeon Kim (S)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.

Hong-Hee Won (HH)

Samsung Advanced Institute for Health Sciences and Technology (SAIHST), Sungkyunkwan University, Samsung Medical Center, Seoul, South Korea.

Ruth J F Loos (RJF)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Judy Cho (J)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Louis R Pasquale (LR)

Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Eye and Vision Research Institute, New York Eye and Ear Infirmary of Mount Sinai, New York, New York, USA.

Girish N Nadkarni (GN)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Hasso Plattner Institute for Digital Health at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Ghislain Rocheleau (G)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.

Ron Do (R)

Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
BioMe Phenomics Center, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, New York, USA.
ORCID: 0000-0002-3144-3627

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Troubles du rythme cardiaque › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Isomerases › Helicase › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Enzymes de réparation de l'ADN › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Phénomènes génétiques › Structures génétiques › Génome › Exome › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Phénomènes génétiques › Phénotype › Pléiotropie › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines nucléaires › Protéines liant le poly-adp-ribose › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Maladies de l'oeil › Rétinopathies › Dégénérescence de la rétine › Dystrophies rétiniennes › Genetic pleiotropy of ERCC6 loss-of-function...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Séquençage de l'exome › Genetic pleiotropy of ERCC6 loss-of-function...