GDAP2 was first reported in relation to autosomal recessive spinocerebellar ataxia in 2018 (Eidhof et al., PMID: 30084953) in which two female patients presented with late onset gait ataxia, speech changes, cognitive impairment, spasticity, and cerebellar atrophy and were found to have biallelic null variants in the GDAP2 gene. Variants in this gene have been reported in at least four probands in three publications (PMIDs: 30084953, 32437512, 32428220). The mechanism of pathogenicity is reported to be loss of function as the probands affected with cerebellar ataxia all have biallelic nonsense or frameshift variants in GDAP2. This gene-disease relationship is also supported by an animal model study by Eidhof et al. in which knockdown of the Gdap2 gene in Drosophila flies caused abnormal motor behavior, decreased the life span of mutant flies, and increased susceptibility to oxidative stress and starvation (PMID: 30084953). In summary, there is strong evidence to support the relationship between GDAP2 and autosomal recessive spinocerebellar ataxia. Three years must elapse from the first proposal of the assertion to reach a definitive classification without any valid contradictory evidence. We will re-evaluate this gene-disease relationship at that time to determine if an upgraded classification of definitive is warranted. This classification was approved by the ClinGen Cerebellar Ataxia GCEP on the meeting date December 11, 2024 (SOP Version 11).
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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