CADM1 – Autism Spectrum Disorder

Two heterozygous missense mutations in CADM1, c.736C>A (p.His246Asn) and c.752A>C (p.Tyr251Ser), were identified in two unrelated ASD families (2 probands; segregation across multiple affected relatives) (PMID:18957284). Functional assays demonstrated that both variants disrupt the third Ig-like domain, leading to defective glycosylation, impaired trafficking to the cell surface, and increased susceptibility to proteolysis (PMID:18957284). Subsequent studies revealed that mutated CADM1 induces endoplasmic reticulum stress, reduces homophilic interactions, and impairs synaptogenesis in neuronal models, accompanied by upregulation of CHOP, an ER stress marker, supporting a pathogenic mechanism involving synaptic dysfunction (PMID:21364653). In a cohort of 3,195 Chinese patients with neurodevelopmental disorders, CADM1 was prioritized among six ASD-associated genes based on high co-expression and interaction with known ASD genes, further implicating CADM1 in ASD susceptibility (PMID:33994118). Collectively, these findings provide limited but consistent evidence for CADM1’s role in ASD etiology, integrating familial segregation and concordant cellular dysfunction. Key take-home: CADM1 is a candidate ASD gene acting through impaired synaptic adhesion and ER stress, meriting further clinical and molecular validation.

References

• Biochemical and biophysical research communications • 2008 • Mutations in the gene encoding CADM1 are associated with autism spectrum disorder. PMID:18957284
• Cell death & disease • 2010 • Autism spectrum disorder is related to endoplasmic reticulum stress induced by mutations in the synaptic cell adhesion molecule, CADM1. PMID:21364653
• Journal of genetics and genomics = Yi chuan xue bao • 2021 • Targeted sequencing and integrative analysis of 3,195 Chinese patients with neurodevelopmental disorders prioritized 26 novel candidate genes. PMID:33994118

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