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 language | English |
|---|---|
| Pages (from-to) | 1427-1431 |
| Journal | American Journal of Medical Genetics, Part A |
| Volume | 176 |
| Issue number | 6 |
| DOIs | |
| Publication status | Published - 2018 |
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Keywords
- Gillespie
- ITPR1
- Next generation sequencing
- Spinocerebellar ataxia
- Splicing
ASJC Scopus subject areas
- Genetics
- Genetics(clinical)
Cite this
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; Esposito, Susanna; Cinnante, Claudia Maria; Tabano, Silvia Maria; Miozzo, Monica Rosa.
In: American Journal of Medical Genetics, Part A, Vol. 176, No. 6, 2018, p. 1427-1431.Research output: Contribution to journal › Article
}
TY - JOUR
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.
KW - Gillespie
KW - ITPR1
KW - Next generation sequencing
KW - Spinocerebellar ataxia
KW - Splicing
UR - http://www.scopus.com/inward/record.url?scp=85045714139&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85045714139&partnerID=8YFLogxK
U2 - 10.1002/ajmg.a.38704
DO - 10.1002/ajmg.a.38704
M3 - Article
VL - 176
SP - 1427
EP - 1431
JO - American Journal of Medical Genetics, Part A
JF - American Journal of Medical Genetics, Part A
SN - 1552-4825
IS - 6
ER -