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Expanding the clinical and genetic spectrum of FDXR deficiency by functional validation of variants of uncertain significance
Author(s) -
Stenton Sarah L.,
PiekutowskaAbramczuk Dorota,
Kulterer Lea,
Kopajtich Robert,
Claeys Kristl G.,
Ciara Elżbieta,
Eisen Johannes,
Płoski Rafał,
Pronicka Ewa,
Malczyk Katarzyna,
Wagner Matias,
Wortmann Saskia B.,
Prokisch Holger
Publication year - 2021
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.24160
Subject(s) - biology , missense mutation , exome sequencing , clinical significance , human genetics , genetics , phenotype , biomarker , disease , atrophy , bioinformatics , pathology , gene , medicine
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 Here, we identified seven unpublished patients with FDXR deficiency belonging to six independent families.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.