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

Leda Paganini, Chiara Pesenti, Donatella Milani, Laura Fontana, Silvia Motta, Silvia Maria Sirchia, Giulietta Scuvera, Paola Marchisio, Susanna Esposito, Claudia Maria Cinnante, Silvia Maria Tabano, Monica Rosa Miozzo

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Pages (from-to)1427-1431
JournalAmerican Journal of Medical Genetics, Part A
Issue number6
Publication statusPublished - 2018


  • Gillespie
  • ITPR1
  • Next generation sequencing
  • Spinocerebellar ataxia
  • Splicing

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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