Introduction

We aimed to identify the underlying genetic cause of a cerebellar ataxia and early-onset retinal dystrophy (EORD) phenotype in a child of consanguineous origin.

Results

The child had hypotonia from the age of 3 months and developmental delay mainly in gross motor skills with a rather static neurological course. Neurological examination demonstrated multidirectional nystagmus, truncal hypotonia and ataxia. Fundoscopy showed pigmentary abnormalities, electroretinography (ERG) demonstrated reduced scotopic and photopic amplitudes and brain MRI showed cerebellar atrophy.

Homozygosity mapping revealed a homozygous deletion of exon 2 of the GRID2 gene in the proband, leading to an in-frame deletion (p.Gly30_Glu81del). This deletion is the human counterpart of the natural mouse hotfoot mutant ho15J, disrupting exon 2 of Grid2. We demonstrated GRID2 mRNA expression in human cerebellum, and retina and GRID2 protein expression in both murine and human retina. Whole exome sequencing (WES) did not reveal disease-causing mutations in known RD or other genes, supporting the neurological and retinal phenotype as a single clinical entity.

Conclusions

Human GRID2 deletions have only recently been described in recessive cerebellar ataxia1. Hotfoot mice are characterized by cerebellar ataxia and are caused by different Grid2 deletions. We identified (mRNA and protein expression studies) for the first time, GRID2 as an underlying disease gene in cerebellar ataxia and EORD. Interestingly, a CRX-bound cis-regulatory element (retina-specific transcription factor Crx) of GRID2 was removed by the deletion in our patient.  Our study expands the expression domain of GRID2 and the clinical spectrum of GRID2 hotfoot deletion mutants in human.