ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000021.8) (NC_000021.9)
  • Haploinsufficiency score: 1
  • Strength of Evidence (disclaimer): Little evidence for dosage pathogenicity
Evidence for haploinsufficiency phenotype
PubMed ID Description
24463507 Fromer et al Nature 2014: Loss-of-function mutation reported in schizophrenia cohort identified through exome sequencing of 623 trios. Found 1 de novo nonsense SNV within ITSN1 in a male (Supp Table 1) with schizophrenia. Proband age of onset of disease was 23 years. Additional phenotype details were not provided but mentioned that loss-of-function?de novo?mutations were more common in patients with relatively poor school performance. Authors also took the genes in their subset with schizophrenia and overlapped them with genes containing de novo mutations in ASD and intellectual disability; but did not find an overlap for ITSN1 (see Fig. 1b).
25621899 Yuen et al., Nat Med.?2015 Authors used whole-genome sequencing (WGS) of 85 quartet families (parents and two ASD-affected siblings), consisting of 170 individuals with ASD. All ASD subjects were diagnosed using clinical evaluation and the Autism Diagnostic Interview protocols -- details on specific phenotype or severity not provided. A de novo frameshift insertion exonic mutation was detected (supp table 3) in ITSN1 in 1 individual. Authors consider this as a novel putative ASD candidate risk gene
24458657 Fukai et al 2014 Am J Med Gen A: This publication highlights a case report on a 1.4 Mb deletion CNV overlapping intersectin 1 gene in a boy with growth, developmental delays, and microcephaly. Among the 17 CNV cases reported, the intersectin 1 gene (ITSN1, NM_003024.2) was commonly deleted or disrupted (Fig 2A). ?10 of the 17 patients shared various brain structural anomalies, Minimal region of overlap includes part of?ITSN1. Homozygous?Itsn1?mutant mice have a smaller brain as a percentage of body mass compared with wild?type mice and Itsn1?null mice also showed agenesis of the corpus callosum. The authors ?propose that haploinsufficiency of the?ITSN1?gene is associated with developmental delay, microcephaly, and brain structural anomalies.

Haploinsufficiency phenotype comments:

The intersectin 1, ITSN1, gene has been implicated in ASD/ID by large-scale WES/WGS studies and/or meta-analysis from the Autism Sequencing Consortium. This gene has not shown recurrent de novo SNV mutations in the cases reported with schizophrenia and/or autism. A haploinsufficiency model has been proposed by 1 study with ITSN1 being in smallest region of overlap (PMID: 24458657 ). However, focal deletions of ITSN1 have not been described. Additional literature: PMID: 29302074: Hu et al (2017) studied 404 consanguineous ID families, ?with microcephaly being present in almost half of the families. A splice site disease causing variant was found in ITSN1 (Table S1), reported as a novel ID disability gene. This splice site variant was in a 4 Mb region of homozygosity. Given the substantial genetic heterogeneity that exists in ASD and schizophrenia and with the mutation burden emerging for ITSN1, it is currently considered a novel susceptibility risk gene for ASD/ID and schizophrenia.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

Triplosensitivity phenotype comment:

To date, no gross duplications/insertions cataloged in HGMD. And with the exception of segmental trisomies of chromosome 21 containing this gene in individuals with neurodevelopmental and partial dysmorphologic features of Downs (e.g PMID: 27840696) , specific gain of function and/or focal duplications of ITSN1 leading to a neurodevelopmental phenotype have not been reported