ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

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Evidence for Loss Phenotypes

Evidence for loss of function 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.

Evidence for Triplosenstive Phenotype

NOTE:The loss of function score should be used to evaluate deletions, and the triplosensitivity score should be used to evaluated duplications. CNVs encompassing more than one gene must be evaluated in their totality (e.g. overall size, gain vs. loss, presence of other genes, etc). The rating of a single gene within the CNV should not necessarily be the only criteria by which one defines a clinical interpretation. Individual interpretations must take into account the phenotype described for the patient as well as issues of penetrance and expressivity of the disorder. ACMG has published guidelines for the characterization of postnatal CNVs, and these recommendations should be utilized (Genet Med (2011)13: 680-685). Exceptions to these interpretive correlations will occur, and clinical judgment should always be exercised.