ITPR1-associated spinocerebellar ataxia with craniofacial features-additional evidence for germline mosaicism

Abstract

Inositol 1,4,5-triphosphate receptor type 1 (ITPR1) is an endoplasmic reticulum-bound intracellular inositol triphosphate receptor involved in the regulation of intracellular calcium. Pathogenic variants in ITPR1 are associated with spinocerebellar ataxia (SCA) types 15/16 and 29 and have recently been implicated in a facial microsomia syndrome. In this report, we present a family with three affected individuals found to have a heterozygous missense c.800C > T (predicted p.Thr267Met) who present clinically with a SCA29-like syndrome. All three individuals presented with varying degrees of ataxia, developmental delay, and apparent intellectual disability, as well as craniofacial involvement-an uncommon finding in patients with SCA29. The variant was identified using clinical exome sequencing and validated with Sanger sequencing. It is presumed to be inherited via parental germline mosaicism. We present our findings to provide additional evidence for germline mosaic inheritance of SCA29, as well as to expand the clinical phenotype of the syndrome.

Keywords: ataxia; frontal bossing; gaze-evoked horizontal nystagmus; intellectual disability; leukocoria; limb dysmetria; microcephaly; moderate; moderate global developmental delay.