Dataset Information

Genetic diagnosis of Mendelian disorders via RNA sequencing.

ABSTRACT: Across a variety of Mendelian disorders, ?50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We find a median of one aberrantly expressed gene, five aberrant splicing events and six mono-allelically expressed rare variants in patient-derived fibroblasts and establish disease-causing roles for each kind. Private exons often arise from cryptic splice sites providing an important clue for variant prioritization. One such event is found in the complex I assembly factor TIMMDC1 establishing a novel disease-associated gene. In conclusion, our study expands the diagnostic tools for detecting non-exonic variants and provides examples of intronic loss-of-function variants with pathological relevance.

SUBMITTER: Kremer LS

PROVIDER: S-EPMC5499207 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Genetic diagnosis of Mendelian disorders via RNA sequencing.

Kremer Laura S LS Bader Daniel M DM Mertes Christian C Kopajtich Robert R Pichler Garwin G Iuso Arcangela A Haack Tobias B TB Graf Elisabeth E Schwarzmayr Thomas T Terrile Caterina C Koňaříková Eliška E Repp Birgit B Kastenmüller Gabi G Adamski Jerzy J Lichtner Peter P Leonhardt Christoph C Funalot Benoit B Donati Alice A Tiranti Valeria V Lombes Anne A Jardel Claude C Gläser Dieter D Taylor Robert W RW Ghezzi Daniele D Mayr Johannes A JA Rötig Agnes A Freisinger Peter P Distelmaier Felix F Strom Tim M TM Meitinger Thomas T Gagneur Julien J Prokisch Holger H

Nature communications 20170612

Across a variety of Mendelian disorders, ∼50-75% of patients do not receive a genetic diagnosis by exome sequencing indicating disease-causing variants in non-coding regions. Although genome sequencing in principle reveals all genetic variants, their sizeable number and poorer annotation make prioritization challenging. Here, we demonstrate the power of transcriptome sequencing to molecularly diagnose 10% (5 of 48) of mitochondriopathy patients and identify candidate genes for the remainder. We ...[more]

PMID: 28604674

Similar Datasets

Project description:ImportanceClinical exome sequencing (CES) is rapidly becoming a common molecular diagnostic test for individuals with rare genetic disorders.ObjectiveTo report on initial clinical indications for CES referrals and molecular diagnostic rates for different indications and for different test types.Design, setting, and participantsClinical exome sequencing was performed on 814 consecutive patients with undiagnosed, suspected genetic conditions at the University of California, Los Angeles, Clinical Genomics Center between January 2012 and August 2014. Clinical exome sequencing was conducted as trio-CES (both parents and their affected child sequenced simultaneously) to effectively detect de novo and compound heterozygous variants or as proband-CES (only the affected individual sequenced) when parental samples were not available.Main outcomes and measuresClinical indications for CES requests, molecular diagnostic rates of CES overall and for phenotypic subgroups, and differences in molecular diagnostic rates between trio-CES and proband-CES.ResultsOf the 814 cases, the overall molecular diagnosis rate was 26% (213 of 814; 95% CI, 23%-29%). The molecular diagnosis rate for trio-CES was 31% (127 of 410 cases; 95% CI, 27%-36%) and 22% (74 of 338 cases; 95% CI, 18%-27%) for proband-CES. In cases of developmental delay in children (<5 years, n = 138), the molecular diagnosis rate was 41% (45 of 109; 95% CI, 32%-51%) for trio-CES cases and 9% (2 of 23, 95% CI, 1%-28%) for proband-CES cases. The significantly higher diagnostic yield (P value = .002; odds ratio, 7.4 [95% CI, 1.6-33.1]) of trio-CES was due to the identification of de novo and compound heterozygous variants.Conclusions and relevanceIn this sample of patients with undiagnosed, suspected genetic conditions, trio-CES was associated with higher molecular diagnostic yield than proband-CES or traditional molecular diagnostic methods. Additional studies designed to validate these findings and to explore the effect of this approach on clinical and economic outcomes are warranted.

Dataset Information

Genetic diagnosis of Mendelian disorders via RNA sequencing.

Publications

Genetic diagnosis of Mendelian disorders via RNA sequencing.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets