Haploinsufficiency, de novo and biallelic missense variants in CSMD2 are associated with neurodevelopmental disorders

CSMD2

Biallelic and de novo missense CSMD2 variants clustering in two regions, with impaired membrane localization and cytoplasmic aggregation; haploinsufficiency through truncating variants

The CSMD1-3 paralogs are GWAS-associated with cognition, ADHD and schizophrenia, and rare biallelic variants have been linked to epilepsy. The authors identify nine individuals from eight families carrying biallelic CSMD2 missense variants in developmental delay/intellectual disability cohorts, with autism spectrum disorder (ASD), ADHD and brain anomalies. They also report two families with monoallelic frameshift variants and two cases of de novo missense variants, compared with twelve de novo cases from published trio analyses. In silico modelling and immunofluorescence show impaired membrane localization of the mutated proteins, and csmd2 zebrafish crispants show microcephaly, a smaller cerebellum and reduced connectivity.

Synthesis written by Geno'X. For the full original abstract, please refer to the source publication.

The gene is not new as such, but this work proposes both recessive and dominant forms, which calls for replication, all the more as it is a preprint not yet peer-reviewed. The UK Biobank enrichment is only nominally significant and should not be over-interpreted. For exome/genome, the issue is how to interpret CSMD2 variants found in routine rather than adding it to a gene list.

Analysis by Dr Thibaut Benquey