Department of Medical Genetics, Ankara City Hospital, Ankara, Turkey.
Faculty of Medicine, Department of Child Neurology, Karadeniz Technical University, Trabzon, Turkey.
Acta Neurol Belg. 2021 Dec;121(6):1457-1462. doi: 10.1007/s13760-020-01328-z. Epub 2020 Mar 13.
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.
常染色体隐性小脑共济失调（ARCA）的特征是小脑和脊髓的结构异常。脊髓小脑共济失调 18 型（MIM 616204）是 ARCA 之一，是由于缺失导致 GRID2 基因的功能丧失突变引起的。GRID2 的错义突变导致具有功能获得机制的共济失调。我们报告了两兄弟中儿童期发病的共济失调中 GRID2 的纯合性重复。对其中一个兄弟进行了临床外显子组测序。临床外显子组测试未报告致病突变。使用 Affymetrix Optima 芯片对整个家族进行了染色体微阵列分析。染色体微阵列分析显示，两个兄弟姐妹均存在 GRID2（arr[GRCh37]4q22.2(94426536_94613158)×4）的~121-kb 纯合重复，包括外显子 14，这是一种常染色体隐性（功能丧失）和常染色体半显性（功能获得）形式的共济失调。据我们所知，这是首次发现 GRID2 的纯合性重复导致 GluRD2 蛋白功能丧失。这些发现使我们得出结论，拷贝数变异分析应该是常染色体隐性共济失调类型的诊断过程的一部分。
