A cryptic pathogenic NDUFV1 variant identified by RNA-seq in a patient with normal complex I activity in muscle and transient magnetic resonance imaging changes.
NDUFV1
RNA
complex I deficiency
mitochondrial
Journal
American journal of medical genetics. Part A
ISSN: 1552-4833
Titre abrégé: Am J Med Genet A
Pays: United States
ID NLM: 101235741
Informations de publication
Date de publication:
06 2023
06 2023
Historique:
revised:
18
01
2023
received:
20
11
2022
accepted:
15
02
2023
medline:
11
5
2023
pubmed:
11
3
2023
entrez:
10
3
2023
Statut:
ppublish
Résumé
Mitochondrial respiratory chain disorders (MRC) are amongst the most common group of inborn errors of metabolism. MRC, of which complex I deficiency accounts for approximately a quarter, are very diverse, causing a wide range of clinical problems and can be difficult to diagnose. We report an illustrative MRC case whose diagnosis was elusive. Clinical signs included failure to thrive caused by recurrent vomiting, hypotonia and progressive loss of motor milestones. Initial brain imaging suggested Leigh syndrome but without expected diffusion restriction. Muscle respiratory chain enzymology was unremarkable. Whole-genome sequencing identified a maternally inherited NDUFV1 missense variant [NM_007103.4 (NDUFV1):c.1157G > A; p.(Arg386His)] and a paternally inherited synonymous variant [NM_007103.4 (NDUFV1):c.1080G > A; (p.Ser360=)]. RNA sequencing demonstrated aberrant splicing. This case emphasizes the diagnostic odyssey of a patient in whom a confirmed diagnosis was elusive because of atypical features and normal muscle respiratory chain enzyme (RCE) activities, along with a synonymous variant, which are often filtered out from genomic analyses. It also illustrates the following points: (1) complete resolution of magnetic resonance imaging changes may be part of the picture in mitochondrial disease; (2) analysis for synonymous variants is important for undiagnosed patients; and (3) RNA-seq is a powerful tool to demonstrate pathogenicity of putative splicing variants.
Identifiants
pubmed: 36896486
doi: 10.1002/ajmg.a.63170
doi:
Substances chimiques
NDUFV1 protein, human
0
Electron Transport Complex I
EC 7.1.1.2
Types de publication
Case Reports
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1599-1606Subventions
Organisme : NHGRI NIH HHS
ID : UM1 HG008900
Pays : United States
Informations de copyright
© 2023 Wiley Periodicals LLC.
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