Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance.
Hum Mutat
; 42(3): 310-319, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33348459
ABSTRACT
Ferrodoxin reductase (FDXR) deficiency is a mitochondrial disease described in recent years primarily in association with optic atrophy, acoustic neuropathy, and developmental delays. Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families. These patients show a broad clinical spectrum ranging from Leigh syndrome with early demise and severe infantile-onset encephalopathy, to milder movement disorders. In total nine individual pathogenic variants, of which seven were novel, were identified in FDXR using whole exome sequencing in suspected mitochondrial disease patients. Over 80% of these variants are missense, a challenging variant class in which to determine pathogenic consequence, especially in the setting of nonspecific phenotypes and in the absence of a reliable biomarker, necessitating functional validation. Here we implement an Arh1-null yeast model to confirm the pathogenicity of variants of uncertain significance in FDXR, bypassing the requirement for patient-derived material.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Doença de Leigh
/
Atrofia Óptica
/
Doenças Mitocondriais
Limite:
Humans
Idioma:
En
Revista:
Hum Mutat
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Alemanha