A novel de novo intronic variant in ITPR1 causes Gillespie syndrome.

Autor: Keehan L; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Jiang MM; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Li X; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Marom R; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Dai H; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics, Houston, Texas, USA., Murdock D; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Liu P; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Baylor Genetics, Houston, Texas, USA., Hunter JV; Texas Children's Hospital, Houston, Texas, USA.; Department of Radiology, Baylor College of Medicine, Houston, Texas, USA., Heaney JD; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Robak L; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Emrick L; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA.; Department of Pediatrics, Baylor College of Medicine (BCM), Houston, Texas, USA.; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, Texas, USA., Lotze T; Texas Children's Hospital, Houston, Texas, USA.; Department of Pediatrics, Baylor College of Medicine (BCM), Houston, Texas, USA.; Division of Neurology and Developmental Neuroscience, Department of Pediatrics, BCM, Houston, Texas, USA., Blieden LS; Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA., Lewis RA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA.; Cullen Eye Institute, Department of Ophthalmology, Baylor College of Medicine, Houston, Texas, USA., Levin AV; Flaum Eye Institute and Golisano Children's Hospital, Departments of Ophthalmology and Pediatrics, University of Rochester, Rochester, New York, USA., Capasso J; Flaum Eye Institute and Golisano Children's Hospital, Departments of Ophthalmology and Pediatrics, University of Rochester, Rochester, New York, USA., Craigen WJ; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Rosenfeld JA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA., Lee B; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA., Burrage LC; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, USA.; Texas Children's Hospital, Houston, Texas, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2021 Aug; Vol. 185 (8), pp. 2315-2324. Date of Electronic Publication: 2021 May 05.
DOI: 10.1002/ajmg.a.62232
Abstrakt: 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.
(© 2021 Wiley Periodicals LLC.)
Databáze: MEDLINE
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