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Panel-Based Nuclear and Mitochondrial Next-Generation Sequencing Outcomes of an Ethnically Diverse Pediatric Patient Cohort with Mitochondrial Disease

Lookup NU author(s): Dr Joanna Elson, Professor Francois van der Westhuizen



This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).


© 2019 American Society for Investigative Pathology and the Association for Molecular Pathology Mitochondrial disease (MD) is a group of rare inherited disorders with clinical heterogeneous phenotypes. Recent advances in next-generation sequencing (NGS) allow for rapid genetic diagnostics in patients who experience MD, resulting in significant strides in determining its etiology. This, however, has not been the case in many patient populations. We report on a molecular diagnostic study using mitochondrial DNA and targeted nuclear DNA (nDNA) NGS of an extensive cohort of predominantly sub-Saharan African pediatric patients with clinical and biochemically defined MD. Patients in this novel cohort presented mostly with muscle involvement (73%). Of the original 212 patients, a muscle respiratory chain deficiency was identified in 127 cases. Genetic analyses were conducted for these 127 cases based on biochemical deficiencies, for both mitochondrial (n = 123) and nDNA using panel-based NGS (n = 86). As a pilot investigation, whole-exome sequencing was performed in a subset of African patients (n = 8). These analyses resulted in the identification of a previously reported pathogenic mitochondrial DNA variant and seven pathogenic or likely pathogenic nDNA variants (ETFDH, SURF1, COQ6, RYR1, STAC3, ALAS2, and TRIOBP), most of which were identified via whole-exome sequencing. This study contributes to knowledge of MD etiology in an understudied, ethnically diverse population; highlights inconsistencies in genotype-phenotype correlations; and proposes future directions for diagnostic approaches in such patient populations.

Publication metadata

Author(s): Schoonen M, Smuts I, Louw R, Elson JL, van Dyk E, Jonck L-M, Rodenburg RJT, van der Westhuizen FH

Publication type: Article

Publication status: Published

Journal: Journal of Molecular Diagnostics

Year: 2019

Volume: 21

Issue: 3

Pages: 503-513

Print publication date: 01/05/2019

Online publication date: 11/03/2019

Acceptance date: 06/02/2019

Date deposited: 21/01/2020

ISSN (print): 1525-1578

ISSN (electronic): 1943-7811

Publisher: Elsevier BV


DOI: 10.1016/j.jmoldx.2019.02.002

PubMed id: 30872186


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