title: Transition to next generation analysis of the whole mitochondrial genome: a summary of molecular defects.
abstract: The diagnosis of mitochondrial disorders is challenging because of the clinical variability and genetic heterogeneity. Conventional analysis of the mitochondrial genome often starts with a screening panel for common mitochondrial DNA (mtDNA) point mutations and large deletions (mtScreen). If negative, it has been traditionally followed by Sanger sequencing of the entire mitochondrial genome (mtWGS). The recently developed "Next-Generation Sequencing" (NGS) technology offers a robust high-throughput platform for comprehensive mtDNA analysis. Here, we summarize the results of the past 6 years of clinical practice using the mtScreen and mtWGS tests on 9,261 and 2,851 unrelated patients, respectively. A total of 344 patients (3.7%) had mutations identified by mtScreen and 99 (3.5%) had mtDNA mutations identified by mtWGS. The combinatorial analyses of mtDNA and POLG revealed a diagnostic yield of 6.7% in patients with suspected mitochondrial disorders but no recognizable syndromes. From the initial mtWGS-NGS cohort of 391 patients, 21 mutation-positive cases (5.4%) have been identified. The mtWGS-NGS provides a one-step approach to detect common and uncommon point mutations, as well as deletions. Additionally, NGS provides accurate, sensitive heteroplasmy measurement, and the ability to map deletion breakpoints. A new era of more efficient molecular diagnosis of mtDNA mutations has arrived.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas 77030, USA.
authors: Sha
authors: S
authors: Tang
authors: Jing
authors: J
authors: Wang
authors: Victor Wei
authors: VW
authors: Zhang
authors: Fang-Yuan
authors: FY
authors: Li
authors: Megan
authors: M
authors: Landsverk
authors: Hong
authors: H
authors: Cui
authors: Cavatina K
authors: CK
authors: Truong
authors: Guoli
authors: G
authors: Wang
authors: Li Chieh
authors: LC
authors: Chen
authors: Brett
authors: B
authors: Graham
authors: Fernando
authors: F
authors: Scaglia
authors: Eric S
authors: ES
authors: Schmitt
authors: William J
authors: WJ
authors: Craigen
authors: Lee-Jun C
authors: LJ
authors: Wong
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D017353:Gene Deletion; D054629:Genome, Mitochondrial; D023281:Genomics; D006239:Haplotypes; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism; D028361:Mitochondrial Diseases / Q000175:diagnosis* / Q000235:genetics*; D009154:Mutation; D059645:Mutation Rate; D055815:Young Adult