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
27824329 Study sequences 189 autism risk genes in a 1,543 Chinese ASD probands (1,045 from trios). Two de novo DSCAM disrupting variants (defined as nonsense, frameshift or splice site) in 1,086 Chinese ASD trios. Also one maternally inherited DSCAM disrupting variant (maternal phenotype unclear). Also, 20 missense variants, mostly inherited.
25363768 Simons Simplex Collection exome paper, >2500 autism simplex families. Exomes for 2,508 affected children (& parents) and 1,911 unaffected siblings. Three de novo DSCAM disrupting variants in probands (and one de novo missense in an unaffected sibs).
25363760 Autism Sequencing Consortium 2014 paper. Exomes of 3,871 autism cases and 9,937 ancestry-matched or parental controls. One case de novo loss of function, one control loss of function. Controls: 2672 UK 10K case-control - healthy individuals from two intensively studied British cohorts of European ancestry, namely the Avon Longitudinal Study of Parents and Children (ALSPAC)13 and TwinsUK14 2526 Swedish controls - controls were randomly selected from Swedish population registers. Control inclusion criteria: never hospitalized for schizophrenia or bipolar disorder, both parents born in Scandinavia, age?18 years. 861 ARRA Autism Sequencing Consortium case-control - unrelated cases and controls. In total 6059 unrelated controls.

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.