Autosomal recessive spinocerebellar ataxia 18 caused by homozygous exon 14 duplication in GRID2 and review of the literature.

Autosomal recessive cerebellar ataxias (ARCA) are characterized by the abnormal structure of the cerebellum and spinal cord. Spinocerebellar ataxia type 18 (MIM 616204), one of the ARCA, is caused by the loss-of-function mutations of the GRID2 gene due to deletions. Missense mutations in the GRID2 cause ataxia with the gain-of-function mechanism. We report a homozygous GRID2  duplication in childhood-onset ataxia in two siblings. The clinical exome sequencing was performed on one of the siblings. No disease-causing mutations were reported as a result of the clinical exome test. Chromosomal microarray analysis was performed on the entire family using Affymetrix Optima chips. Chromosomal microarray analysis showed a ~ 121-kb homozygous duplication of GRID2 (arr[GRCh37]4q22.2(94426536_94613158) × 4), including exon 14, in both siblings. Previously, GRID2 has been associated with an autosomal recessive (loss-of-function) and autosomal semi-dominant (gain-of-function) forms of ataxia. To the best of our knowledge, this is the first study to identify a homozygous duplication of GRID2 causing loss of function of the GluRD2 protein. These findings provide us with the conclusion that copy number variation analyses should be in the diagnostic process of autosomal recessive ataxia types.