ClinGen Dosage Sensitivity Curation Page


Curation Status: Complete

Gene Information

Location Information

Evidence for Loss Phenotypes

Evidence for loss of function phenotype
PubMed ID Description
24853937 Takata 2014 reports 2 de novo loss of function mutations among 231 patients with schizophrenia phenotype from exome sequencing data. No loss of function variants found in the 34 controls. The two patients with the mutations also had obsessive compulsive disorder.
26974950 Singh 2016 investigated several different patient cohorts (schizophrenia and patient groups with developmental delays). In the schizophrenia cohorts, they observed a total of 10 loss-of-function mutations at least 4 of which were de novo. Statistical analysis of case versus controls were significant for elevation of SETD1A LOF mutations. In the developmental delay cohorts, 6 additional LOF mutations were detected. Two had unknown inheritance, 2 were de novo and 2 were maternally inherited without clinical information on the mothers. In total 16 SETD1A LOF of function mutations were identified in patients with at least 6 de novo mutations. Only two LOF mutations observed among 58,404 controls (both in ExAC). Based on the phenotypes of the patients, the full clinical spectrum associated with SETD1A LOF mutations is yet to be determined, but includes schizophrenia, likely developmental delay, and possibly facial dysmorphism, epilepsy and personality disorder.

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.