A genome-first approach to aggregating rare genetic variants in LMNA for association with electronic health record phenotypes.

Genetics in Medicine : Official Journal of the American College of Medical Genetics
Joseph ParkDaniel J Rader

Abstract

"Genome-first" approaches, in which genetic sequencing is agnostically linked to associated phenotypes, can enhance our understanding of rare variants' contributions to disease. Loss-of-function variants in LMNA cause a range of rare diseases, including cardiomyopathy. We leveraged exome sequencing from 11,451 unselected individuals in the Penn Medicine Biobank to associate rare variants in LMNA with diverse electronic health record (EHR)-derived phenotypes. We used Rare Exome Variant Ensemble Learner (REVEL) to annotate rare missense variants, clustered predicted deleterious and loss-of-function variants into a "gene burden" (N = 72 individuals), and performed a phenome-wide association study (PheWAS). Major findings were replicated in DiscovEHR. The LMNA gene burden was significantly associated with primary cardiomyopathy (p = 1.78E-11) and cardiac conduction disorders (p = 5.27E-07). Most patients had not been clinically diagnosed with LMNA cardiomyopathy. We also noted an association with chronic kidney disease (p = 1.13E-06). Regression analyses on echocardiography and serum labs revealed that LMNA variant carriers had dilated cardiomyopathy and primary renal disease. Pathogenic LMNA variants are an underdiagnosed cause of...Continue Reading

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Citations

Sep 11, 2020·Current Cardiology Reports·Nosheen Reza, Anjali Tiku Owens
Sep 30, 2020·Genetics in Medicine : Official Journal of the American College of Medical Genetics·Brittany M WengerBruce D Gelb
Jun 19, 2020·Journal of Personalized Medicine·Nicolas Vignier, Antoine Muchir
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Mar 22, 2021·Human Genetics·Shadi AhmadmehrabiDaniel J Rader
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Jul 21, 2021·Otolaryngology--head and Neck Surgery : Official Journal of American Academy of Otolaryngology-Head and Neck Surgery·Shadi AhmadmehrabiJason Brant

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Methods Mentioned

BETA
exome sequencing

Software Mentioned

SIFT
MutationTaster
gnomAD
PheWAS
R package “ PheWAS ”
SAS
REVEL
R
DiscovEHR
LRT

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