DSCAM – Autism Spectrum Disorder

Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by impairments in social communication and repetitive behaviors. The Down Syndrome Cell Adhesion Molecule (DSCAM) is a transmembrane cell‐surface receptor that guides neuronal self‐avoidance, axon outgrowth, and synaptic specificity during central nervous system development. DSCAM has been implicated as an ASD risk gene through large‐scale sequencing studies of affected trios.

In a Chinese ASD cohort, targeted sequencing of 189 candidate genes in 1,543 probands (1,045 trios) revealed an 11-fold enrichment of de novo likely gene-disruptive (LGD) variants compared with neutral expectation. DSCAM was among the top recurrently hit genes, with multiple unrelated probands carrying de novo LGD events (PMID:27824329). These variants support an autosomal dominant, haploinsufficiency mechanism.

Although segregation data in multiplex ASD families are lacking, the identification of independent de novo LGD variants in DSCAM underscores its role in ASD etiology. No common variant associations or founder alleles have been reported.

Functional assays in mouse and Drosophila models demonstrate that loss or mutation of DSCAM disrupts neural circuit formation. A mouse Dscam(R1018P) substitution impairs protein localization to filopodia and blocking of DSCAM cleavage, phenocopying aspects of Dscam null alleles (PMID:23300735). In Drosophila, Vap‐33 is required for axonal trafficking of Dscam isoforms, linking DSCAM dysfunction to neurodevelopmental deficits (PMID:23197716).

No studies to date report conflicting genetic evidence for DSCAM in ASD, and model‐organism phenotypes—while not specific to ASD behavioral outcomes—are concordant with a loss-of-function mechanism in neural development.

Overall, recurrent de novo LGD variants in DSCAM combined with convergent functional data from animal models support a Moderate clinical validity for the DSCAM–ASD association. DSCAM should be included in diagnostic sequencing panels for ASD to enhance variant interpretation.

References

• Nature communications • 2016 • De novo genic mutations among a Chinese autism spectrum disorder cohort. PMID:27824329
• PloS one • 2012 • A novel mouse Dscam mutation inhibits localization and shedding of DSCAM. PMID:23300735
• The Journal of neuroscience • 2012 • Drosophila Vap-33 is required for axonal localization of Dscam isoforms. PMID:23197716

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