A novel homozygous synonymous splicing variant in SELENOI gene causes Spastic Paraplegia 81.

Abstract

Hereditary spastic paraplegia-81 is a recently identified, rare autosomal recessive disease, caused due to biallelic pathogenic variants in the SELENOI gene, with only two families reported to date. The features documented in the two previous affected families include sensorineural deafness, blindness, cleft palate, delayed motor development, regression of motor skills, impaired intellectual development, poor speech and language acquisition, spasticity, hyperreflexia, white matter abnormalities, and cerebral and cerebellar atrophy. In the present study, we performed exome sequencing analysis in a single-family with two affected siblings to identify the genetic cause of complicated hereditary spastic paraplegia. The results were further confirmed by Sanger sequencing, cDNA analysis and 3D protein modelling. Exome sequencing identified a homozygous, synonymous variant in the SELENOI gene (NM_033505.4:c.126G>A:p.(Lys42Lys) in both the siblings. Sanger sequencing confirmed the heterozygous status in both parents consistent with the autosomal recessive inheritance. This variant has been found to disrupt normal splicing and is likely to lead to skipping of exon 2, causing in-frame deletion of SELENOI N-terminal 23 amino acids[NM_033505.4:c.57_126del:p.(Tyr20_Lys42del)] further leading to the structural changes in the protein. We report a novel homozygous synonymous variant in the SELENOI gene causing abnormal splicing in two patients affected with Hereditary spastic paraplegia-81. This report further expands the phenotypic and genotypic spectrum of Hereditary spastic paraplegia-81.