Document Type
Article
Publication Date
2-1-2026
Original Citation
Ordaz T,
Sundaramurthi J,
Arterbery A,
Bagley A,
Gargano M,
Bauer J,
Danis D,
Giampietro P,
Raney E,
Rekerle L,
Shingle M,
Davids J,
Robinson P.
An ITPR1 Variant in the IP3-ITPR1 Binding Pocket Associated With a Clinical Phenotype of Athetoid Cerebral Palsy. Am J Med Genet A. 2026;200(2):459–67
Keywords
JGM, Humans, Binding Sites, Cerebral Palsy, Genetic Association Studies, Inositol 1, 4, 5-Trisphosphate, Inositol 1, 4, 5-Trisphosphate Receptors, Mutation, Missense, Pedigree, Phenotype, Protein Binding, Spinocerebellar Ataxias, Whole Genome Sequencing
JAX Source
Am J Med Genet A. 2026;200(2):459–67
ISSN
1552-4833
PMID
40968496
DOI
https://doi.org/10.1002/ajmg.a.64263
Grant
This study was supported by a grant from Shriners Children's Clinical Research grant #70904. Additional funding was received from the National Institutes of Health (NIH), National Institute of Child Health and Human Development 1R01HD103805, and NIH, National Human Genome Research Institute (5RM1HG010860 and 5U24HG011449).
Abstract
A de novo, missense variant in ITPR1-inositol 1,4,5-trisphosphate receptor type 1 (ITPR1), p.(Tyr567Cys), was identified by trio whole-genome sequencing in an individual diagnosed with Spinocerebellar ataxia 29 (SCA29) who was affected by cerebral palsy and global developmental delay. The variant affects a residue involved in Inositol 1,4,5-trisphosphate (IP3)-ITPR1 binding. Genotype-Phenotype correlation analysis of the set of missense variants affecting nine residues involved in IP3-ITPR1 binding in the current case and 170 reports of individuals with ITPR1 variants showed a significantly higher frequency of phenotypic features related to neurodevelopmental delay in these variants than in other ITPR1 variants. Our proband was diagnosed with cerebral palsy, as were five other published individuals diagnosed with SCA29. Two of these individuals were siblings who were found to have the variant p.(Arg269Trp), also located in the IP3-ITPR1 binding pocket. These observations suggest that genotype-phenotype correlations exist in the ITPR1 gene and underscore the importance of data sharing and reuse to elucidate the natural history of rare neurodevelopmental diseases.
Creative Commons License
This work is licensed under a Creative Commons Attribution 4.0 International License.