The relationship between GFER and GFER-related primary mitochondrial disease was evaluated using the ClinGen Clinical Validity Framework as of September 28, 2023. GFER encodes growth factor ERV1-like and functions in the Disulfide Relay System (DRS, PMID: 19409522). Alterations in this protein lead to impaired mitochondrial transport of several DRS substrates, with subsequent decreased activities of the respiratory chain including complex IV.
GFER was first reported in relation to autosomal recessive GFER-related primary mitochondrial disease in 2009 (PMID: 19409522). GFER has been associated with a single disease entity to date, autosomal recessive myopathy, mitochondrial progressive, with congenital cataract and developmental delay [OMIM#613076]. This is one disease entity according to the ClinGen Lumping and Splitting Framework, and has been renamed as GFER-related primary mitochondrial disease.
Evidence supporting this gene-disease relationship includes case-level data and experimental data. This curation included five variants (one missense, two frameshift, two termination) in four probands from three publications (PMIDs: 19409522, 26018198, 28155230). Age of onset was in the neonatal period. Clinical features in affected individuals include cataracts, ptosis, hearing loss, hypotonia, developmental delay, myopathy, epilepsy, and dysautonomia. Muscle biopsies show COX-negative fibers, ragged red fibers, abnormal mitochondrial morphology, and mitochondrial respiratory chain enzyme deficiencies.
The mechanism of disease is loss of function. This gene-disease association is also supported by its known biochemical function, functional alteration in non-patient cells, rescue in patient cells, and model systems (PMIDs: 19409522).
In summary, there is definitive evidence to support the relationship between GFER and GFER-related primary mitochondrial disease. This relationship has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the NICHD/NINDS U24 ClinGen Mitochondrial Disease Gene Curation Expert Panel on September 28, 2023 (SOP Version 10).
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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