Subscribe to RSS
DOI: 10.1055/s-0039-1693150
Gillespie's Syndrome with Minor Cerebellar Involvement and No Intellectual Disability Associated with a Novel ITPR1 Mutation: Report of a Case and Literature Review
Publication History
26 January 2019
29 May 2019
Publication Date:
24 July 2019 (online)
![](https://www.thieme-connect.de/media/neuropediatrics/201906/lookinside/thumbnails/10-1055-s-0039-1693150_192124sc-1.jpg)
Abstract
Variants in the inositol 1,4,5-trisphosphate receptor type 1 (ITPR1) gene have been recently identified as a cause of Gillespie's syndrome, a rare inherited condition characterized by bilateral iris hypoplasia, congenital muscle hypotonia, nonprogressive cerebellar ataxia, and intellectual disability. Here, we describe the clinical and genetic findings in a patient who presented with iris hypoplasia, mild gait ataxia, atrophy of the anterior cerebellar vermis but no cognitive deficits. Whole-exome sequencing (WES) uncovered a heterozygous ITPR1 p.Glu2094Lys missense variant, affecting a highly conserved glutamic acid residue for which other amino acid substitutions have already been reported in Gillespie's syndrome patients. Our data expand both the phenotypic and genetic spectrum associated with Gillespie's syndrome and suggest a mutation hotspot on Glu2094.
-
References
- 1 Crawfurd MD, Harcourt RB, Shaw PA. Non-progressive cerebellar ataxia, aplasia of pupillary zone of iris, and mental subnormality (Gillespie's syndrome) affecting 3 members of a non-consanguineous family in 2 generations. J Med Genet 1979; 16 (05) 373-378
- 2 Gillespie FD. Aniridia, cerebellar ataxia and oligophrenia in siblings. Arch Ophthalmol 1965; 73: 338-341
- 3 Nelson J, Flaherty M, Grattan-Smith P. Gillespie syndrome: a report of two further cases. Am J Med Genet 1997; 71 (02) 134-138
- 4 McEntagart M, Williamson KA, Rainger JK. , et al; DDD Study. A restricted repertoire of de novo mutations in ITPR1 cause Gillespie syndrome with evidence for dominant-negative effect. Am J Hum Genet 2016; 98 (05) 981-992
- 5 Gerber S, Alzayady KJ, Burglen L. , et al. Recessive and dominant de novo itpr1 mutations cause Gillespie syndrome. Am J Hum Genet 2016; 98 (05) 971-980
- 6 Berridge MJ. Inositol trisphosphate and calcium signalling. Nature 1993; 361 (6410): 315-325
- 7 van de Leemput J, Chandran J, Knight MA. , et al. Deletion at ITPR1 underlies ataxia in mice and spinocerebellar ataxia 15 in humans. PLoS Genet 2007; 3 (06) e108
- 8 Huang L, Chardon JW, Carter MT. , et al. Missense mutations in ITPR1 cause autosomal dominant congenital nonprogressive spinocerebellar ataxia. Orphanet J Rare Dis 2012; 7: 67
- 9 Ansari M, Rainger J, Hanson IM. , et al. Genetic analysis of ‘PAX6-negative’ individuals with aniridia or Gillespie syndrome. PLoS One 2016; 11 (04) e0153757
- 10 Dentici ML, Barresi S, Nardella M. , et al. Identification of novel and hotspot mutations in the channel domain of ITPR1 in two patients with Gillespie syndrome. Gene 2017; 628: 141-145
- 11 Carvalho DR, Medeiros JEG, Ribeiro DSM, Martins BJAF, Sobreira NLM. Additional features of Gillespie syndrome in two Brazilian siblings with a novel ITPR1 homozygous pathogenic variant. Eur J Med Genet 2018; 61 (03) 134-138
- 12 Paganini L, Pesenti C, Milani D. , et al. A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome. Am J Med Genet A 2018; 176 (06) 1427-1431
- 13 De Silva D, Williamson KA, Dayasiri KC. , et al. 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. BMC Pediatr 2018; 18 (01) 308
- 14 Hall HN, Williamson KA, FitzPatrick DR. The genetic architecture of aniridia and Gillespie syndrome. Hum Genet 2018; ; (e-pub ahead of print) DOI: 10.1007/s00439-018-1934-8.