Children’s Nutrition Research Center Staff Publications
Language
English
Publication Date
10-1-2023
Journal
Annals of Neurology
DOI
10.1002/ana.26716
PMID
37255483
PMCID
PMC10763625
PubMedCentral® Posted Date
10-1-2024
PubMedCentral® Full Text Version
Author MSS
Abstract
Objective: Primary mitochondrial diseases (PMDs) are heterogeneous disorders caused by inherited mitochondrial dysfunction. Classically defined neuropathologically as subacute necrotizing encephalomyelopathy, Leigh syndrome spectrum (LSS) is the most frequent manifestation of PMD in children, but may also present in adults. A major challenge for accurate diagnosis of LSS in the genomic medicine era is establishing gene-disease relationships (GDRs) for this syndrome with >100 monogenic causes across both nuclear and mitochondrial genomes.
Methods: The Clinical Genome Resource (ClinGen) Mitochondrial Disease Gene Curation Expert Panel (GCEP), comprising 40 international PMD experts, met monthly for 4 years to review GDRs for LSS. The GCEP standardized gene curation for LSS by refining the phenotypic definition, modifying the ClinGen Gene-Disease Clinical Validity Curation Framework to improve interpretation for LSS, and establishing a scoring rubric for LSS.
Results: The GDR with LSS across the nuclear and mitochondrial genomes was classified as definitive for 31 of 114 GDRs curated (27%), moderate for 38 (33%), limited for 43 (38%), and disputed for 2 (2%). Ninety genes were associated with autosomal recessive inheritance, 16 were maternally inherited, 5 were autosomal dominant, and 3 were X-linked.
Interpretation: GDRs for LSS were established for genes across both nuclear and mitochondrial genomes. Establishing these GDRs will allow accurate variant interpretation, expedite genetic diagnosis of LSS, and facilitate precision medicine, multisystem organ surveillance, recurrence risk counseling, reproductive choice, natural history studies, and determination of eligibility for interventional clinical trials.
Keywords
Child, Humans, Leigh Disease, Mitochondrial Diseases, Mitochondria
Published Open-Access
yes
Recommended Citation
McCormick, Elizabeth M; Keller, Kierstin; Taylor, Julie P; et al., "Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum" (2023). Children’s Nutrition Research Center Staff Publications. 260.
https://digitalcommons.library.tmc.edu/staff_pub/260
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Biochemical Phenomena, Metabolism, and Nutrition Commons, Dietetics and Clinical Nutrition Commons, Endocrinology, Diabetes, and Metabolism Commons, Neurology Commons, Neurosciences Commons, Nutrition Commons