Gillespie syndrome (GLSP) is a rare congenital disorder characterized by partial aniridia, hypotonia, progressive cerebellar hypoplasia, nonprogressive ataxia, and intellectual disability. All causative variants to date affect the central or the 3'-terminal domains of ITPR1 gene and exhibit autosomal recessive or dominant inheritance pattern. We investigated by exome sequencing the molecular cause of GLSP in a family composed by consanguineous healthy parents, two affected siblings and one healthy son. We found the novel splice site variant c.278_279 + 2delACGT located at the 5'-end of ITPR1. The affected siblings were homozygotes, their parents heterozygous carriers and the variant was absent in the healthy son, indicating a recessive inheritance pattern. The deletion abolished the splice-donor site at exon 5/intron 5 junction, causing the skipping of exon 5 and the generation of a premature STOP codon. The mutation is predicted to result in the synthesis of a 64-amino acids nonfunctional protein. The mutant transcript comprised >96% of ITPR1 mRNA in the affected siblings, indicating that a small amount of wild-type transcript was still present. The novel autosomal recessive mutation here reported is the first variant affecting the ITPR1 N-terminal suppressor domain, thus extending the spectrum of the pathogenetic variants in GLSP and the range of the associated clinical manifestations.

A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome / Paganini, L; Pesenti, C; Milani, D; Fontana, L; Motta, S; Sirchia, Sm; Scuvera, G; Marchisio, P; Esposito, S; Cinnante, Cm; Tabano, Sm; Miozzo, Mr. - In: AMERICAN JOURNAL OF MEDICAL GENETICS. PART A. - ISSN 1552-4825. - 176:6(2018), pp. 1427-1431. [10.1002/ajmg.a.38704]

A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome

Esposito S;
2018-01-01

Abstract

Gillespie syndrome (GLSP) is a rare congenital disorder characterized by partial aniridia, hypotonia, progressive cerebellar hypoplasia, nonprogressive ataxia, and intellectual disability. All causative variants to date affect the central or the 3'-terminal domains of ITPR1 gene and exhibit autosomal recessive or dominant inheritance pattern. We investigated by exome sequencing the molecular cause of GLSP in a family composed by consanguineous healthy parents, two affected siblings and one healthy son. We found the novel splice site variant c.278_279 + 2delACGT located at the 5'-end of ITPR1. The affected siblings were homozygotes, their parents heterozygous carriers and the variant was absent in the healthy son, indicating a recessive inheritance pattern. The deletion abolished the splice-donor site at exon 5/intron 5 junction, causing the skipping of exon 5 and the generation of a premature STOP codon. The mutation is predicted to result in the synthesis of a 64-amino acids nonfunctional protein. The mutant transcript comprised >96% of ITPR1 mRNA in the affected siblings, indicating that a small amount of wild-type transcript was still present. The novel autosomal recessive mutation here reported is the first variant affecting the ITPR1 N-terminal suppressor domain, thus extending the spectrum of the pathogenetic variants in GLSP and the range of the associated clinical manifestations.
2018
A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome / Paganini, L; Pesenti, C; Milani, D; Fontana, L; Motta, S; Sirchia, Sm; Scuvera, G; Marchisio, P; Esposito, S; Cinnante, Cm; Tabano, Sm; Miozzo, Mr. - In: AMERICAN JOURNAL OF MEDICAL GENETICS. PART A. - ISSN 1552-4825. - 176:6(2018), pp. 1427-1431. [10.1002/ajmg.a.38704]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11381/2864766
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