Gillespie syndrome in a South Asian child: a case report with confirmation of a heterozygous mutation of the ITPR1 gene and review of the clinical and molecular features

Abstract

BackgroundGillespie 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.Case presentationA 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.ConclusionThe 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.

Disease-associated mutations in inositol 1,4,5-trisphosphate receptor subunits impair channel function

“…B , disease-associated mutations found in the regulatory and coupling domain ( 47 – 49 , 52 – 54 , 65 , 72 73 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 82 ). C, disease-associated mutations found in the C-terminal domain ( 52 53 , 54 55 , 65 , 83 84 , 85 , 86 , 87 , 88 89 ). Diseases associated with mutations in at least one isoform of IP 3 R include SCA29 ( blue ), Gillespie syndrome ( orange ), anhidrosis ( pink ), neuropathy ( green ), pontocerebellar hypoplasia ( dark blue ), spinocerebellar ataxia 15/16 ( light blue ), head and neck squamous cell carcinoma ( red ), Sézary Syndrome ( purple ), and familial isolated primary hyperparathyroidism ( gray ).…”

Whole‐genome analysis identifying candidate genes of altitude adaptive ecological thresholds in yak populations

“…However, a small ZHp in the ITPR1 region from the current study indicated species specificity in plateau adaptive molecular mechanisms. Furthermore, recent reported heterozygous mutations and structural variants of ITPR1 genes are associated with the development of ataxia in the brains of human children (De Silva et al, ; Synofzik et al, ). As we know, plateau hypoxic environmental stimulation leads to an increase in the ratio of [HCO3‐]/[H2CO3] in the cerebrospinal fluid of animals, leading to the inhibition of central chemoreceptors, thus resulting in brain ataxia (Hainsworth, Drinkhil, & Rivera‐Chira, ).…”

Gillespie's Syndrome with Minor Cerebellar Involvement and No Intellectual Disability Associated with a Novel ITPR1 Mutation: Report of a Case and Literature Review

“…So far, 25 genetically confirmed patients with Gillespie's syndrome have been reported. [10][11][12][13][14] In total, 12 mutations have been identified, including dominant and recessive variants. The mutations found in Gillespie's syndrome are, with one exception, localized either in the regulatory domain or in the C-terminal transmembrane domain of ITPR1 (►Fig.…”