Autosomal recessive cerebellar ataxia-27 caused by a novel loss-of-function variant of ganglioside-induced differentiation associated protein 2 in a Spanish family

Background and ObjectivesOur aim has been to describe a patient with a novel loss-of-function variant of the ganglioside-induced differentiation associated protein 2 (GDAP2) gene in homozygosis causing autosomal recessive cerebellar ataxia.MethodsWe studied the virtual gene panel of hereditary ataxia with onset in adulthood (version 4.15) of PanelApp by means of whole exome sequencing. The validation of the variant of interest found was performed by Sanger sequencing. A segregation study was performed on family members.ResultsThe patient is a man who started at age 32 years with dysarthria soon followed by cerebellar ataxia. On evolution, spasticity, cervical dystonia, and cognitive impairment were observed. A premature stop codon variant was detected in homozygosity in exon 2 of the GDAP2 gene: c.57_59delinsACCCCAGCT (p.Trp19*). It was also detected in the patient's mother and brother, who were heterozygous, and 4 nephews on the paternal side, who were also carriers of the variant.DiscussionThis null variant in the GDAP2 gene has not been previously described in the literature associated to ataxia, neither is it present in population databases. It is considered probably pathogenic (PVS1 and PM2) and as such can be classified from this study, providing further evidence on the association of GDAP2 with hereditary cerebellar ataxia.