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.
Am J Med Genet A
; 191(6): 1599-1606, 2023 06.
Article
en En
| MEDLINE
| ID: mdl-36896486
ABSTRACT
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.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Imagen por Resonancia Magnética
/
Músculos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Am J Med Genet A
Asunto de la revista:
GENETICA MEDICA
Año:
2023
Tipo del documento:
Article
País de afiliación:
Australia