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A novel splice site variant in ITPR1 gene underlying recessive Gillespie syndrome
Author(s) -
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
Publication year - 2018
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.38704
Subject(s) - exon , genetics , biology , splice site mutation , mutation , splice , intron , gene , exome sequencing , hypotonia , rna splicing , alternative splicing , rna
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.