The association of early-onset non-progressive ataxia and miosis is an extremely rare phenotypic entity occasionally reported in the literature. To date, only one family (two siblings and their mother) has benefited from a genetic diagnosis by the identification of a missense heterozygous variant (p.Arg36Cys) in the ITPR1 gene. This gene encodes the inositol 1,4,5-trisphosphate receptor type 1, an intracellular channel that mediates calcium release from the endoplasmic reticulum. Deleterious variants in this gene are known to be associated with two types of spinocerebellar ataxia, SCA15 and SCA29, and with Gillespie syndrome that is associated with ataxia, partial iris hypoplasia, and intellectual disability. In this work, we describe a novel individual carrying a heterozygous missense variant (p.Arg36Pro) at the same position in the N-terminal suppressor domain of ITPR1 as the family previously reported, with the same phenotype associating early-onset non-progressive ataxia and miosis. This second report confirms the implication of ITPR1 in the miosis-ataxia syndrome and therefore broadens the clinical spectrum of the gene. Moreover, the high specificity of the phenotype makes it a recognizable syndrome of genetic origin.

BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 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.
OBJECTIVE: 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: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -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.

Gillespie syndrome, a genetically inherited condition, is described as a disease that primarily affects the ocular and associated nervous systems. It is characterized by a clinical triad of bilateral aniridia, intellectual disability, and cerebellar ataxia, and is inherited in an autosomal dominant or recessive fashion. The most well-studied mutations related to this syndrome affect the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). Gillespie syndrome is an exceptionally uncommon diagnosis with less than 50 patients ever being diagnosed. We present a case of a patient with bilateral aniridia and ataxia but lacking intellectual disability, and moreover had no known family history of this syndrome. Our case report shows that Gillespie syndrome may not necessarily present with the classic \"triad\" of symptoms as previously described in the literature.

Congenital aniridia is a rare panocular disease defined by a national diagnostic and care protocol (PNDS) validated by the HAS. In most cases, it is due to an abnormality in the PAX6 gene, located at 11p13. Aniridia is a potentially blinding autosomal dominant disease with high penetrance. The prevalence varies from 1/40,000 births to 1/96,000 births. Approximately one third of cases are sporadic. Ocular involvement includes complete or partial absence of iris tissue, corneal opacification with neovascularization, glaucoma, cataract, foveal hypoplasia, optic disc hypoplasia and ptosis. These ocular disorders coexist to varying degrees and progress with age. Congenital aniridia manifests in the first months of life as nystagmus, visual impairment and photophobia. A syndromic form such as WAGR syndrome, WAGRO syndrome (due to the risk of renal Wilms tumor) or Gillespie syndrome (cerebellar ataxia) must be ruled out. Systemic associations may include diabetes, due to expression of the PAX6 gene in the pancreas, as well as other extraocular manifestations. Initial assessment is best carried out in a referral center specialized in rare ophthalmologic diseases, with annual follow-up. The management of progressive ocular involvement must be both proactive and responsive, with medical and surgical management. Visual impairment and photophobia result in disability, leading to difficulties in mobility, movement, communication, learning, fine motor skills, and autonomy, with consequences in personal, school, professional, socio-cultural and athletic life. Medico-socio-educational care involves a multidisciplinary team. Disability rehabilitation must be implemented to prevent and limit situations of handicap in activities of daily living, relying on the Commission for the Rights and Autonomy of People with Disabilities (CDAPH) within the Departmental House of People with Disabilities (MDPH). The general practitioner coordinates multidisciplinary medical and paramedical care.

A 10-year-old girl presented with left-eye esotropia and fixed mydriasis. Previously, she had been diagnosed with cerebellar ataxia and mild intellectual disability. Her parents were healthy. She was found to have partial aniridia of the pupillary sphincter bilaterally. A next-generation sequencing test for the inositol 1,4,5-trisphosphate type 1 receptor (ITPR1) gene was performed, revealing a previously unreported homozygous variant of uncertain significance at c.7610. Computational (In Silico) predictive models predicted this variant to be disease causing. With the arrival of DNA sequencing, aniridia can be genetically classified. In this case report, we present a patient with phenotypic features of Gillespie\'s syndrome with a homozygous variant in the ITPR1 gene that has not previously been reported.

Mutations in ITPR1 cause ataxia and aniridia in individuals with Gillespie syndrome (GLSP). However, the pathogenic mechanisms underlying aniridia remain unclear. We identified a de novo GLSP mutation hotspot in the 3\'-region of ITPR1 in five individuals with GLSP. Furthermore, RNA-sequencing and immunoblotting revealed an eye-specific transcript of Itpr1, encoding a 218amino acid isoform. This isoform is localized not only in the endoplasmic reticulum, but also in the nuclear and cytoplasmic membranes. Ocular-specific transcription was repressed by SOX9 and induced by MAF in the anterior eye segment (AES) tissues. Mice lacking seven base pairs of the last Itpr1 exon exhibited ataxia and aniridia, in which the iris lymphatic vessels, sphincter and dilator muscles, corneal endothelium and stroma were disrupted, but the neural crest cells persisted after completion of AES formation. Our analyses revealed that the 218-amino acid isoform regulated the directionality of actin fibers and the intensity of focal adhesion. The isoform might control the nuclear entry of transcriptional regulators, such as YAP. It is also possible that ITPR1 regulates both AES differentiation and muscle contraction in the iris.

Gillespie syndrome (GLSP) is characterized by bilateral symmetric partial aplasia of the iris presenting as a fixed and large pupil, cerebellar hypoplasia with ataxia, congenital hypotonia, and varying levels of intellectual disability. GLSP is caused by either biallelic or heterozygous, dominant-negative, pathogenic variants in ITPR1. Here, we present a 5-year-old male with GLSP who was found to have a heterozygous, de novo intronic variant in ITPR1 (NM_001168272.1:c.5935-17G > A) through genome sequencing (GS). Sanger sequencing of cDNA from this individual\'s fibroblasts showed the retention of 15 nucleotides from intron 45, which is predicted to cause an in-frame insertion of five amino acids near the C-terminal transmembrane domain of ITPR1. In addition, qPCR and cDNA sequencing demonstrated reduced expression of both ITPR1 alleles in fibroblasts when compared to parental samples. Given the close proximity of the predicted in-frame amino acid insertion to the site of previously described heterozygous, de novo, dominant-negative, pathogenic variants in GLSP, we predict that this variant also has a dominant-negative effect on ITPR1 channel function. Overall, this is the first report of a de novo intronic variant causing GLSP, which emphasizes the utility of GS and cDNA studies for diagnosing patients with a clinical presentation of GLSP and negative clinical exome sequencing.

Gillespie syndrome is a rare, congenital, neurological disorder characterized by the association of partial bilateral aniridia, non-progressive cerebellar ataxia and intellectual disability. Homozygous and heterozygous pathogenic variants of the ITPR1 gene encoding an inositol 1, 4, 5- triphosphate- responsive calcium channel have been identified in 13 patients recently. There have been 22 cases reported in the literature by 2016, mostly from the western hemisphere with none reported from Sri Lanka.
A 10-year-old girl born to healthy non-consanguineous parents with delayed development is described. She started walking unaided by 9 years with a significantly unsteady gait and her speech was similarly delayed. Physical examination revealed multiple cerebellar signs. Slit lamp examination of eyes revealed bilateral partial aniridia. Magnetic resonance imaging of brain at the age of 10 years revealed cerebellar (mainly vermian) hypoplasia. Genetic testing confirmed the clinical suspicion and demonstrated a heterozygous pathogenic variant c.7786_7788delAAG p.(Lys2596del) in the ITPR1 gene.
The report of this child with molecular confirmation of Gillespie syndrome highlights the need for careful evaluation of ophthalmological and neurological features in patients that enables correct clinical diagnosis. The availability of genetic testing enables more accurate counseling of the parents and patients regarding recurrence risks to other family members.

Ca2+ signaling governs a diverse range of cellular processes and, as such, is subject to tight regulation. A main component of the complex intracellular Ca2+-signaling network is the inositol 1,4,5-trisphosphate (IP3) receptor (IP3R), a tetrameric channel that mediates Ca2+ release from the endoplasmic reticulum (ER) in response to IP3. IP3R function is controlled by a myriad of factors, such as Ca2+, ATP, kinases and phosphatases and a plethora of accessory and regulatory proteins. Further complexity in IP3R-mediated Ca2+ signaling is the result of the existence of three main isoforms (IP3R1, IP3R2 and IP3R3) that display distinct functional characteristics and properties. Despite their abundant and overlapping expression profiles, IP3R1 is highly expressed in neurons, IP3R2 in cardiomyocytes and hepatocytes and IP3R3 in rapidly proliferating cells as e.g. epithelial cells. As a consequence, dysfunction and/or dysregulation of IP3R isoforms will have distinct pathophysiological outcomes, ranging from neurological disorders for IP3R1 to dysfunctional exocrine tissues and autoimmune diseases for IP3R2 and -3. Over the past years, several IP3R mutations have surfaced in the sequence analysis of patient-derived samples. Here, we aimed to provide an integrative overview of the clinically most relevant mutations for each IP3R isoform and the subsequent molecular mechanisms underlying the etiology of the disease.

Gillespie syndrome (GS) [MIM: 206700] is a very rare condition characterized by bilateral iris defect, congenital hypotonia, cerebellar ataxia and intellectual disability. The typical iris anomaly is considered necessary to the diagnosis of GS. Recently, variants in ITPR1 were described causing GS. Non-neurological features were reported in few patients. Here we describe two consanguineous siblings with GS and a novel homozygous ITPR1 pathogenic variant (p.N984fs). They also present a cardiac defect (pulmonary valve stenosis) and one sib had a genitourinary malformation (ureteropelvic junction obstruction). Our report reinforces ITPR1 as the cause of GS and suggests a possible role of ITPR1 in the development of other organs.