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Validation and clinical performance of a combined nuclear‐mitochondrial next‐generation sequencing and copy number variant analysis panel in a Canadian population
Author(s) -
Levy Michael A,
Kerkhof Jennifer,
Belmonte Frances R.,
Kaufman Brett A.,
Bhai Pratibha,
Brady Lauren,
Bursztyn Lulu L.C.D.,
Tarnopolsky Mark,
Rupar Tony,
Sadikovic Bekim
Publication year - 2021
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.61998
Subject(s) - heteroplasmy , mitochondrial dna , biology , copy number variation , genetics , nuclear gene , gene , genome , dna sequencing , mitochondrial disease , computational biology , population , medicine , environmental health
Abstract Diagnosing mitochondrial disorders is a challenge due to the heterogeneous clinical presentation and large number of associated genes. A custom next generation sequencing (NGS) panel was developed incorporating the full mitochondrial genome (mtDNA) plus 19 nuclear genes involved in structural mitochondrial defects and mtDNA maintenance. This assay is capable of simultaneously detecting small gene sequence variations and larger copy number variants (CNVs) in both the nuclear and mitochondrial components along with heteroplasmy detection down to 5%. We describe technical validations of this panel and its implementation for clinical testing in a Canadian reference laboratory, and report its clinical performance in the initial 950 patients tested. Using this assay, we demonstrate a diagnostic yield of 18.1% of patients with known pathogenic variants. In addition to the common 5 kb mtDNA deletion, we describe significant contribution of pathogenic CNVs in both the mitochondrial genome and nuclear genes in this patient population.