ABSTRACT The 1,4,5‐trisphosphate receptor type 1 ( ITPR1 ) gene encodes an endoplasmic reticulum calcium release channel, in which loss‐of‐function mutations have been associated with spinocerebellar ataxias and related neurological phenotypes. Only one gain‐of‐function mutation in the highly conserved suppressor domain of ITPR1 has been previously reported. We report a novel de novo ITPR1 variant (p.(Tyr131His)) detected by whole genome sequencing in a child with an unexplained movement disorder, characterized by tremor and dystonia, concurrent with a second diagnosis of Myhre syndrome. The proband's movement disorder characteristics share much overlap with previously reported individuals with suppressor domain variants; however, she does not have ataxia. We provide functional evidence of this variant's gain‐of‐function consequence via in vitro experiments of inositol 1,4,5‐triphosphate‐mediated calcium release. Our findings deepen the knowledge of ITPR1 ‐mediated movement disorders, expanding the phenotypic spectrum to include movement disorders without ataxia.
Théberge et al. (Fri,) studied this question.