Identification of a Novel GRM1 Frameshift Variant in Two Pakistani Families Broadens the Genetic Landscape of Ultra-Rare Spinocerebellar Ataxia Type 13.

Autosomal recessive spinocerebellar ataxia 13 (SCAR13) is an extremely rare neurodegenerative disorder characterized by psychomotor delay, ranging from mild to severe intellectual disability with absent or poor speech development, nystagmus and stance ataxia. If ambulation is achieved, affected subjects often exhibit gait ataxia. Additionally, epilepsy and polyneuropathy have been reported in some patients. SCAR13 is caused by pathogenic variants in the GRM1 gene, which is predominantly expressed in the cerebellum, with lower levels in the other parts of the brain. To date, only seven reports of this rare ataxia have been published globally. Our study aimed to investigate clinical and mutation spectrum of GRM1-associated SCAR13 disorder in nine patients of two consanguineous Pakistani families (designated here to as NP35 and NP36). We performed whole exome sequencing in the probands of the two families followed by Sanger sequencing to test variant segregation. We identified a novel GRM1 frameshift variant (NM_001278064.2):c.3525_3529del; p.(Asn1176IlefsTer71) in both families as a cause of SCAR13. It was classified as a variant of uncertain significance (PM2: pathogenic moderate 2 and PVS1: pathogenic very strong 1) according to the ACMG guidelines. The novel variant exhibited clinical heterogeneity in the two families. Moreover, scoliosis was observed in all four patients of the family NP35, a feature previously documented in only one patient worldwide. Our study expands the limited mutation spectrum of the GRM1-associated SCAR13. Next-generation sequencing plays a pivotal role in the elucidation of inherited neurological disorders and in a better understanding of the convergent phenotypes.