Lessons learned from additional research analyses of unsolved clinical exome casesReport as inadecuate

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Genome Medicine

, 9:26

First Online: 21 March 2017Received: 05 July 2016Accepted: 08 February 2017DOI: 10.1186-s13073-017-0412-6

Cite this article as: Eldomery, M.K., Coban-Akdemir, Z., Harel, T. et al. Genome Med 2017 9: 26. doi:10.1186-s13073-017-0412-6


BackgroundGiven the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.

MethodsWe designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory i.e. unsolved clinical exomes. Such cases were recruited to a research laboratory for further analyses, in order to potentially: 1 accelerate novel disease gene discovery; 2 increase the molecular diagnostic yield of whole exome sequencing WES; and 3 gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent–offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.

ResultsAnalysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants SNV and copy number variant CNV alleles, yielded a likely contributory variant in 36% 27-74 of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% 38-74 of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30-63 trios 47.6%. Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4-6 singleton cases 66.6%, 1-1 multiplex family involving three affected siblings, and 3-4 75% quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP and increased the number of novel genes, defined in this study as genes identified in more than one family DHX30 and EBF3.

ConclusionAn efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

AbbreviationsAOHAbsence of heterozygosity

ARICAtherosclerosis Risk in Communities

BGBaylor Genetics

BHCMGBaylor-Hopkins Center for Mendelian Genomics

CNVCopy number variant

DD-IDDevelopmental delay-intellectual disability

ExACThe Exome Aggregation Consortium

MAFsMinor allele frequencies

SNVSingle nucleotide variant

UPDUniparental disomy

WESWhole exome sequencing

WGSWhole genome sequencing

Electronic supplementary materialThe online version of this article doi:10.1186-s13073-017-0412-6 contains supplementary material, which is available to authorized users.

Author: Mohammad K. Eldomery - Zeynep Coban-Akdemir - Tamar Harel - Jill A. Rosenfeld - Tomasz Gambin - Asbjørg Stray-Pedersen -

Source: https://link.springer.com/

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