Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum

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. ANN NEUROL 2023;94:696-712.

FIGURE 1.

Mitochondrial Disease Gene Curation Expert Panel (Mito GCEP) curation process overview.

FIGURE 2.

(A). Nuclear (nDNA) and mitochondrial (mtDNA) Gene Genetic Evidence Summary Matrix for LSS curation. This has been amended from Figure 3 in Gene Curation SOP V7 (for nDNA) and SOP V8 (for mtDNA). If score is 0.75, round up to 1. If score is 1.25, round up to 1.5. For mtDNA genes, to score any case, no contradictory evidence can exist such as high allele frequency, homoplasmic occurrences in mitochondrial disease specific databases, or lack of segregation. Mitochondrial guidance is relevant for any variant type. (B). Experimental Evidence Summary Matrix for LSS curation. Function, Functional alteration, and Models – Non-human model organism. No further scoring guidance for rescue experiments was provided as there had been no report of rescue in a human with LSS and other forms of rescue in models were limited. This has been amended from Figure 9 in Gene Curation SOP V7.

FIGURE 3.

Scores for each curated GDR with LSS by Mito GCEP. The default scoring range for a definitive classification is 12–18, moderate is 7–11, and limited is 0.1–6.

FIGURE 4.

LSS Classification Overview by Associated Genome, Association Strength, Score, Time Since Discovery, Gene Class, and Experimental Models. (A) Classifications of nuclear genes (N=98) and mitochondrial DNA genes (N=16) curated for association with LSS. (B) Number of genes reaching definitive, moderate, limited, and disputed classifications for LSS by inheritance pattern. (C) Average scores for each clinical validity classification for LSS. The default scoring range for a definitive classification is 12–18, moderate is 7–11, and limited is 0.1–6. (D) Number of genes first reported to be associated with LSS by year. Genes with a “disputed” classification are excluded. DNM1L is included twice (once for first association with autosomal dominant disease and once for first association with autosomal recessive disease). *The first gene-disease association was reported in 1992. (E) Numbers of experimental models curated. (F) Average curation scores for genes associated with LSS by gene class.