DSCAM

Gene Facts

• HGNC Symbol: DSCAM (HGNC:3039)
• HGNC Name: DS cell adhesion molecule
• Gene type: protein-coding gene
• Locus type: gene with protein product
• Previous symbols: No previous names found
• Alias symbols: CHD2-42, CHD2-52
• %HI: 11.07
• pLI: 1
• LOEUF: 0.28
• Cytoband: 21q22.2
• Genomic Coordinates:

  GRCh37/hg19:	chr21:41382926-42219084
  GRCh38/hg38:	chr21:40010999-40847158

• MANE Select Transcript: NM_001389.5 ENST00000400454.6
• Function: Cell adhesion molecule that plays a role in neuronal self- avoidance. Promotes repulsion between specific neuronal processes of either the same cell or the same subtype of cells. Mediates within retinal amacrine and ganglion cell subtypes both isoneuronal self- avoidance for creating an orderly dendritic arborization and heteroneuronal self-avoidance to maintain the mosaic spacing between amacrine and ganglion cell bodies (PubMed:10925149). Receptor for netrin required for axon guidance independ... (Source: Uniprot)

Dosage Sensitivity Summary (Gene)

• Dosage ID: ISCA-33626
• ClinGen Curation ID: CCID:007035
• Curation Status: Complete
• Issue Type: Dosage Curation - Gene
• Haploinsufficiency: Emerging Evidence for Haploinsufficiency (2)
• Triplosensitivity: No Evidence for Triplosensitivity (0)
• Last Evaluated: 10/10/2023

Haploinsufficiency (HI) Score Details

• HI Score: 2
• HI Evidence Strength: Emerging Evidence for Haploinsufficiency

HI Disease

• autism spectrum disorder

HI Evidence

• PUBMED: 27824329
  Wang et al (2016): Study sequences 189 autism risk genes in 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. One maternally inherited DSCAM disrupting variant was also reported, though the maternal phenotype was unclear. Twenty missense variants were also reported; these were mostly inherited.
• PUBMED: 25363768
  Iossifov et al (2014): This Simons Simplex Collection exome paper describes >2500 autism simplex families. Exomes were available 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 sibling) were reported.
• PUBMED: 25363760
  De Rubeis et al (2014): This Autism Sequencing Consortium paper describes exome results from 3,871 autism cases and 9,937 ancestry-matched or parental controls. One case de novo loss of function and one control loss of function DSCAM variants were described. Control samples included the following: 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, there were 6059 unrelated controls.
• PUBMED: 33004838
  Following on from their 2016 paper above, Wang et al (2020) report another large-scale sequencing study detailing several loss of function DSCAM variants in patients with neurodevelopmental disorders and autism, however many of the same variants are also reported in gnomad (e.g. p.E1474* x2). 'The authors sequence 125 candidate neurodevelopmental disorder risk genes in over 16,000 NDD cases; case-control mutational burden analysis identifies 48 genes with a significant burden of severe ultra-rare mutations'. Their data (combined with previous studies) report 11/19847 likely gene disruptive variants vs 3 in ExAC non-psych subset controls.
• PUBMED: 34312540
  Wilfert et al (2021) using whole-genome sequencing data from 3,474 families, investigated ultra-rare risk variants for autism. They focus on private variants, or ultra-rare variants unique to a family. They reported a DSCAM nonsense (c.3658C>T) and a frameshift variant (c.4776dupG).

• HI Evidence Comments: DSCAM is not currently an OMIM morbid gene but is a proposed risk factor gene for autism based on large-scale sequencing analysis. Loss of function variants have however, been reported in controls (including gnomad), which may be due to reduced penetrance/variable expressivity. Several predicted loss of function nonsense and frameshift variants (some recurrent) are reported in the literature but no whole gene or exonic DSCAM deletions have been reported and therefore other disease mechanism can not be ruled out. Functional study: PMID: 34848499 Chen et al (2022) state 'DSCAM is not only associated with Down syndrome but is also a strong autism risk gene based on large-scale sequencing analysis. However, it remains unknown exactly how DSCAM contributes to autism. In mice, either neuron- and astrocyte-specific or pyramidal neuron-specific DSCAM deficiencies resulted in autism-like behaviors and enhanced spatial memory. In addition, DSCAM knockout or knockdown in pyramidal neurons led to increased dendritic spine maturation. Mechanistically, the extracellular domain of DSCAM binds to NLGN1 and inhibits NLGN1-NRXN1β interaction, which can rescue abnormal spine maturation induced by DSCAM deficiency. Our research demonstrates that DSCAM negatively modulates spine maturation, and that DSCAM deficiency leads to excessive spine maturation and autism-like behaviors, thus providing new insight into a potential pathophysiological mechanism of autism'.

Triplosensitivity (TS) Score Details

• TS Score: 0
• TS Evidence Strength: No Evidence for Triplosensitivity
• TS Evidence Comments: DSCAM is thought to be in the Down Syndrome critical region. There is evidence from animal models that show affects on neurons when present in three copies. There is no literature describing duplication of DSCAM alone in humans to date.