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Interpreting the clinical significance of combined variants in multiple recessive disease genes: systematic investigation of Joubert syndrome yields little support for oligogenicity


Phelps, Ian G; Dempsey, Jennifer C; Grout, Megan E; Isabella, Christine R; Tully, Hannah M; Doherty, Dan; Bachmann-Gagescu, Ruxandra (2017). Interpreting the clinical significance of combined variants in multiple recessive disease genes: systematic investigation of Joubert syndrome yields little support for oligogenicity. Genetics in Medicine:Epub ahead of print.

Abstract

PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4.9% were candidates for di-/oligogenicity, harboring heterozygous RDVs in two or more genes, compared with 4.2-8% in controls (P = 0.66-0.21). Based on Exome Aggregation Consortium (ExAC) allele frequencies, the probability of cumulating RDVs in any two JBTS genes is 9.3%. We found no support for triallelism, as no unaffected siblings carried the same biallelic RDVs as their affected relative. Sixty percent of individuals sharing identical causal RDVs displayed phenotypic discordance. Although 38% of affected individuals harbored RDVs in addition to the causal mutations, their presence did not correlate with phenotypic severity.ConclusionOur data offer little support for triallelism or digenicity/oligogenicity as clinically relevant inheritance modes in JBTS. While phenotypic discordance supports the existence of genetic modifiers, identifying clinically relevant modifiers remains challenging.GENETICS in MEDICINE advance online publication, 3 August 2017; doi:10.1038/gim.2017.94.

Abstract

PurposeNext-generation sequencing (NGS) often identifies multiple rare predicted-deleterious variants (RDVs) in different genes associated with a recessive disorder in a given patient. Such variants have been proposed to contribute to digenicity/oligogenicity or "triallelism" or to act as genetic modifiers.MethodsUsing the recessive ciliopathy Joubert syndrome (JBTS) as a model, we investigated these possibilities systematically, relying on NGS of known JBTS genes in a large JBTS and two control cohorts.Results65% of affected individuals had a recessive genetic cause, while 4.9% were candidates for di-/oligogenicity, harboring heterozygous RDVs in two or more genes, compared with 4.2-8% in controls (P = 0.66-0.21). Based on Exome Aggregation Consortium (ExAC) allele frequencies, the probability of cumulating RDVs in any two JBTS genes is 9.3%. We found no support for triallelism, as no unaffected siblings carried the same biallelic RDVs as their affected relative. Sixty percent of individuals sharing identical causal RDVs displayed phenotypic discordance. Although 38% of affected individuals harbored RDVs in addition to the causal mutations, their presence did not correlate with phenotypic severity.ConclusionOur data offer little support for triallelism or digenicity/oligogenicity as clinically relevant inheritance modes in JBTS. While phenotypic discordance supports the existence of genetic modifiers, identifying clinically relevant modifiers remains challenging.GENETICS in MEDICINE advance online publication, 3 August 2017; doi:10.1038/gim.2017.94.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Institute of Medical Genetics
07 Faculty of Science > Institute of Molecular Life Sciences
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Date:3 August 2017
Deposited On:13 Nov 2017 16:05
Last Modified:19 Feb 2018 09:13
Publisher:Nature Publishing Group
ISSN:1098-3600
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/gim.2017.94
PubMed ID:28771248

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