Robert Kleyner1,2, Nathaniel Ung1, Mohammad Arif1,3, Elaine Marchi1, Karen Amble4, Maureen Gavin4, Ricardo Madrid4 and Gholson Lyon1,4,5 1Department of Human Genetics, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA; 2Department of Neurological Surgery, Renaissance School of Medicine at Stony Brook University, Stony Brook, New York 11794-8122, USA; 3Division of Cytogenetics and Molecular Pathology, North Shore University Hospital, Manhasset, New York 11030, USA; 4George A. Jervis Clinic, NYS Institute for Basic Research in Developmental Disabilities, Staten Island, New York 10314, USA; 5Biology PhD Program, The Graduate Center, The City University of New York, New York, New York 10016, USA Corresponding author: gholsonjlyongmail.com 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.

Received July 5, 2023. Accepted October 2, 2023.