Exome Sequencing in Suspected Monogenic Dyslipidemias

Abstract

Background Exome sequencing is a promising tool for gene mapping in Mendelian disorders. We utilized 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 (LDL) cholesterol (after candidate gene sequencing excluded known genetic causes for high LDL cholesterol families) or high-density lipoprotein (HDL) cholesterol. We used standard analytic approaches to identify candidate variants and also assigned a polygenic score to each individual in order to account for their burden of common genetic variants known to influence lipid levels. In nine 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 three 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 nine 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.

Common and Rare Variant Association Study for Plasma Lipids and Coronary Artery Disease

“…These exome sequencing technologies have already accelerated genetic studies of Mendelian disorders, yielding approximately 20% -30% success in diagnosis, and there is great interest in extending them to complex traits [42][43][44][45] . To address this issue, a large number of strategies, analysis, and interpretation of exome sequencing studies have been proposed [46][47][48][49] , and focused candidate gene sequencing studies have shown some promising results 9,10,[50][51][52][53][54] .…”

Deciphering Unexplained Familial Dyslipidemias

“…In this issue of Circulation: Cardiovascular Genetics, Stitziel and Peloso et al 3 present the results of whole-exome sequencing on 213 family members from 41 kindreds with suspected Mendelian inheritance of either extreme LDL or high-density lipoprotein cholesterol levels. Beforehand, known genetic causes for high LDL cholesterol had been excluded by candidate gene sequencing.…”

“…5 Based on these and other considerations, the European and American guidelines recommend a cascade screening of the entire family for obtaining a molecular diagnosis, identification of all affected family members, and early initiation of medical therapy. 6 In the 8 expert laboratories collaborating with Stitziel et al, 3 such molecular genetic testing for causal mutations had been carried before whole-exome sequencing. Unfortunately, we do not know in how many families candidate gene sequencing had been successful (which precluded them from entering the current study).…”

“…Second, Stitziel et al 3 identified an average of 12 544 nonsynonymous single-nucleotide variants and 802 insertion/deletions-per individual! Thus, rather too many variants than too few were a problem.…”

“…However, because of the small size of the pedigrees studied by Stitziel et al, 3 traditional linkage for obtaining logarithm of the odds scores was not feasible. Thus, given the thousands of private variants present in families, it seems that exome sequencing may compare to loosing sight of the forest for the trees.…”