Journal
CIRCULATION-CARDIOVASCULAR GENETICS
Volume 8, Issue 2, Pages 343-+Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1161/CIRCGENETICS.114.000776
Keywords
DNA sequencing; exome; genetics; human; lipids
Funding
- National Heart Lung and Blood Institute (NHLBI) [K08HL114642]
- Foundation for Barnes-Jewish Hospital
- NHLBI [T32HL007208]
- Massachusetts General Hospital (MGH)
- Howard Goodman Fellowship from MGH
- Donovan Family Foundation [R01 HL107816]
- Fondation Leducq
- Lung Cohorts Sequencing Project [HL-102923]
- WHI Sequencing Project [HL-102924]
- Heart Cohorts Sequencing Project [HL-103010]
- Broad Institute Sequencing Project [HL-102925]
- Northwest Genomics Center Sequencing Project [HL-102926]
- Family Studies Project Team
- PHRC [AOM06024]
- ANR [ANR-05-PCOD-017, ANR-06-MRAR-038, ANR-08-GENO-002-01]
- Conseil de la Recherche de l'Universite Saint-Joseph (Beirut, Lebanon)
- Lifetime Achievement Award of the Dutch Heart Foundation [2010T082]
- NWO [91612122]
- Netherlands CardioVascular Research Initiative [CVON2011-19]
- European Union [FP7-305707, FP7-603091-2]
- Grants-in-Aid for Scientific Research [26461359, 26893094] Funding Source: KAKEN
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Background-Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We used this technique in an attempt to identify novel genes underlying monogenic dyslipidemias. Methods and Results-We performed exome sequencing on 213 selected family members from 41 kindreds with suspected Mendelian inheritance of extreme levels of low-density lipoprotein cholesterol (after candidate gene sequencing excluded known genetic causes for high low-density lipoprotein cholesterol families) or high-density lipoprotein cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual to account for their burden of common genetic variants known to influence lipid levels. In 9 families, we identified likely pathogenic variants in known lipid genes (ABCA1, APOB, APOE, LDLR, LIPA, and PCSK9); however, we were unable to identify obvious genetic etiologies in the remaining 32 families, despite follow-up analyses. We identified 3 factors that limited novel gene discovery: (1) imperfect sequencing coverage across the exome hid potentially causal variants; (2) large numbers of shared rare alleles within families obfuscated causal variant identification; and (3) individuals from 15% of families carried a significant burden of common lipid-related alleles, suggesting complex inheritance can masquerade as monogenic disease. Conclusions-We identified the genetic basis of disease in 9 of 41 families; however, none of these represented novel gene discoveries. Our results highlight the promise and limitations of exome sequencing as a discovery technique in suspected monogenic dyslipidemias. Considering the confounders identified may inform the design of future exome sequencing studies.
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