Expert Panel Curation of 113 Primary Mitochondrial Disease Genes for the Leigh Syndrome Spectrum.
Journal
Annals of neurology
ISSN: 1531-8249
Titre abrégé: Ann Neurol
Pays: United States
ID NLM: 7707449
Informations de publication
Date de publication:
10 2023
10 2023
Historique:
revised:
22
05
2023
received:
16
12
2022
accepted:
23
05
2023
medline:
2
10
2023
pubmed:
31
5
2023
entrez:
31
5
2023
Statut:
ppublish
Résumé
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. 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. 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. 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.
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
696-712Subventions
Organisme : NICHD NIH HHS
ID : U24 HD093483
Pays : United States
Investigateurs
César Augusto Pinheiro Ferreira Alves
(CAPF)
Anna Ardissone
(A)
Renkui Bai
(R)
Isabella Peixoto de Barcelos
(IP)
Enrico Bertini
(E)
Krista Bluske
(K)
John Christodoulou
(J)
Amanda R Clause
(AR)
William C Copeland
(WC)
George A Diaz
(GA)
Daria Diodato
(D)
Matthew C Dulik
(MC)
Greg Enns
(G)
Annette Feigenbaum
(A)
Carl Fratter
(C)
Daniele Ghezzi
(D)
Amy Goldstein
(A)
Andrea Gropman
(A)
Richard Haas
(R)
Amel Karaa
(A)
Mary Kay Koenig
(MK)
Berrin Monteleone
(B)
Sumit Parikh
(S)
Belen Perez Duenas
(BP)
Revathi Rajkumar
(R)
Ann Saada
(A)
Russell P Saneto
(RP)
Kate Sergeant
(K)
John Shoffner
(J)
Conrad Smith
(C)
Christine Stanley
(C)
Isabelle Thiffault
(I)
David Thorburn
(D)
Melissa Walker
(M)
Douglas Wallace
(D)
Lee-Jun Wong
(LJ)
Informations de copyright
© 2023 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.
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