An <scp>ITPR1</scp> Variant in the <scp>IP3</scp> ‐ <scp>ITPR1</scp> Binding Pocket Associated With a Clinical Phenotype of Athetoid Cerebral Palsy

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.

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Publication Details

Journal
American Journal of Medical Genetics Part A
Published
2025-09-18
DOI
https://doi.org/10.1002/ajmg.a.64263
Primary Topic
Genomics and Rare Diseases
Type
article
Field-Weighted Citation Impact
0.00

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article

An ITPR1 Variant in the IP3 ‐ ITPR1 Binding Pocket Associated With a Clinical Phenotype of Athetoid Cerebral Palsy

Jon R. Davids, Mallory Shingle, Anita Bagley, Ellen M. Raney et al.
American Journal of Medical Genetics Part A
Genomics and Rare Diseases
article

An ITPR1 Variant in the IP3 ‐ ITPR1 Binding Pocket Associated With a Clinical Phenotype of Athetoid Cerebral Palsy

Jon R. Davids, Mallory Shingle, Anita Bagley, Ellen M. Raney, Peter N. Robinson, Daniel Daniš, Michael Gargano, Jagadish Chandrabose Sundaramurthi, Jeremy Bauer, Lauren Rekerle, Philip F. Giampietro, Thania Ordaz, Adam S. Arterbery
article en

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.

American Journal of Medical Genetics Part AVol. 200(2)
Shriners Hospitals for Children - Portland (US), University of Illinois Chicago (US), Shriners Hospitals for Children - Mexico (MX), Shriners Hospitals for Children - Northern California (US), Jackson Laboratory (US), Shriners Hospitals for Children - Chicago (US), Berlin Institute of Health at Charité - Universitätsmedizin Berlin (DE)
National Institutes of Health, National Institute of Child Health and Human Development
Openalex Percentile: Top 72%
Genomics and Rare Diseases
DOIOpen Access PDFOpenAlex
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