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
27824329 Wang et al (Nature Comm 2016) performed targeted sequencing using molecular inversion probe technology based on the frequency and severity of de novo variants in autism risk genes previously published from exome studies. A total 1,086 ASD proband?parent trios from the Autism Clinical and Genetic Resources in China were collected. Among this cohort, 1 proband was identified with a confirmed de novo frameshift 1bp deletion in exon 8/17 (from supp table 6). This was not reported in gnomAD.
24463507 Fromer et al (Nature 2014) performed exome sequencing on 623 schizophrenia trios. They found one confirmed de novo frameshift variant in exon 4/17 on the HGDM transcript in an individual with schizophrenia (supp data, details of the phenotype not provided). The authors note that severe gene disruptive variants have a relatively lesser role in schizophrenia as opposed to intellectual disability and/or ASD phenotypes demonstrating more highly conserved mutation hotspots.

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.