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

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1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)1427-1431
JournalAmerican Journal of Medical Genetics, Part A
Volume176
Issue number6
DOIs
Publication statusPublished - 2018

Fingerprint

Recessive Genes
Inheritance Patterns
Exons
Aniridia
Exome
Congenital, Hereditary, and Neonatal Diseases and Abnormalities
RNA Splice Sites
Mutation
Muscle Hypotonia
Homozygote
Ataxia
Codon
Intellectual Disability
Introns
Amino Acids
Messenger RNA
Genes
Aniridia cerebellar ataxia mental deficiency
Proteins

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

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title = "A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome",
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.",
keywords = "Gillespie, ITPR1, Next generation sequencing, Spinocerebellar ataxia, Splicing",
author = "Leda Paganini and Chiara Pesenti and Donatella Milani and Laura Fontana and Silvia Motta and Sirchia, {Silvia Maria} and Giulietta Scuvera and Paola Marchisio and Susanna Esposito and Cinnante, {Claudia Maria} and Tabano, {Silvia Maria} and Miozzo, {Monica Rosa}",
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T1 - A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome

AU - Paganini, Leda

AU - Pesenti, Chiara

AU - Milani, Donatella

AU - Fontana, Laura

AU - Motta, Silvia

AU - Sirchia, Silvia Maria

AU - Scuvera, Giulietta

AU - Marchisio, Paola

AU - Esposito, Susanna

AU - Cinnante, Claudia Maria

AU - Tabano, Silvia Maria

AU - Miozzo, Monica Rosa

PY - 2018

Y1 - 2018

N2 - 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.

AB - 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.

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