ArticleAmerican journal of medical genetics. Part A2021
A novel de novo intronic variant in ITPR1 causes Gillespie syndrome.
Article in American journal of medical genetics. Part A, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02450851 (Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network), which is not on this map. Cited by 10 papers.
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Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Clinical and Genetic Evaluation of Patients With Undiagnosed Disorders Through the Undiagnosed Diseases Network
Who cites it
10 citing papers in PubMed, 17 citations in OpenAlex.
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- Dominant negative ATP5F1A variants disrupt oxidative phosphorylation causing neurological disorders.EMBO molecular medicine · 2025Article
- De novo variants in RYBP are associated with a severe neurodevelopmental disorder and congenital anomalies.Genetics in medicine : official journal of the American College of Medical Genetics · 2025Article
- Article
- Phenotypic Spectrum and Natural History of Gillespie Syndrome. An Updated Literature Review with 2 New Cases.Cerebellum (London, England) · 2024Review
- Exploring the complexity of systemic sclerosis etiology by trio whole genome sequencing.Human molecular genetics · 2024Article
- Congenital anterior segment ocular disorders: Genotype-phenotype correlations and emerging novel mechanisms.Progress in retinal and eye research · 2024Review
- A bird's eye view on the use of whole exome sequencing in rare congenital ophthalmic diseases.Journal of human genetics · 2024Article
- The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing.American journal of human genetics · 2024Article
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Authors and funding
21 authors at 2 institutions in 1 country.
Funding
Abstract
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.
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