Detailed Analysis of <scp><i>ITPR1</i></scp> Missense Variants Guides Diagnostics and Therapeutic Design
Jussi‐Pekka Tolonen, Ricardo Parolin Schnekenberg, Simon J. McGowan, David Sims, Meriel McEntagart, Frances Elmslie, Debbie Shears, Helen Stewart, George K. Tofaris, Tabib Dabir, Patrick J. Morrison, Diana Johnson, Marios Hadjivassiliou, Sian Ellard, Charles Shaw‐Smith, Anna Znaczko, Abhijit Dixit, Mohnish Suri, Ajoy Sarkar, Rachel Harrison, Gabriela Jones, Henry Houlden, G Ceravolo, Joanna Jarvis, Jonathan Williams, Morag Shanks, Penny Clouston, Julia Rankin, Lubov Blumkin, Tally Lerman‐Sagie, Penina Ponger, Salmo Raskin, Katariina Granath, Johanna Uusimaa, Hector Conti, Emma McCann, Shelagh Joss, Alexander J. M. Blakes, Kay Metcalfe, Helen Kingston, Marta Bertoli, Rachel Kneen, Sally Ann Lynch, Inmaculada Martínez Albaladejo, Austen Peter Moore, Wendy D. Jones, Esther B. E. Becker, Andrea H. Németh
Abstract
BACKGROUND: R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.