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 3ʹ-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 5ʹ-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 / L. Paganini, C. Pesenti, D. Milani, L. Fontana, S. Motta, S.M. Sirchia, G. Scuvera, P. Marchisio, S. Esposito, C.M. Cinnante, S.M. Tabano, M.R. Miozzo. - In: AMERICAN JOURNAL OF MEDICAL GENETICS. PART A. - ISSN 1552-4825. - 176:6(2018 Jun), pp. 1427-1431. [10.1002/ajmg.a.38704]

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

Paganini, Leda;Pesenti, Chiara;Milani, Donatella;Fontana, Laura;Motta, Silvia;Sirchia, Silvia Maria;Scuvera, Giulietta;Marchisio, Paola;Cinnante, Claudia Maria;Tabano, Silvia Maria;Miozzo, Monica Rosa
2018-06

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 3ʹ-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 5ʹ-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.
Gillespie; ITPR1; next generation sequencing; spinocerebellar ataxia; splicing; Genetics; Genetics (clinical)
Settore MED/03 - Genetica Medica
Settore MED/38 - Pediatria Generale e Specialistica
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/2434/579649
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