Objectives: we identified an autistic proband with a maternally inherited deletion. Additional studies revealed a non-synonymous polymorphism in one of the genes in the corresponding paternally inherited non-deleted region. Additional murine studies on its expression profile and literature search support the notion that the gene in question may be relevant to the autism phenotype. Methods: Phenotyping: Clinical interview of the proband, his parents and sibs, (DSM-IV interview, the ADI-R and ADOS, and WISC-III). Genotyping: Fluorescent-In-Situ-Hybridization and Comparative Genomic Hybridization (550K Illumina-platform), sequencing of genes in the deleted region. Function and expression: Literature search on (putative) function and interaction. RNA In Situ Hybridization during mouse embryogenesis.
1) The co-occurrence of a deletion involving DIAPH3 and a non-synonymous mutation in the same gene at the non-deleted allele in an autistic proband. While the deletion or mutation are present in his unaffected family members, they never co-occur in the same person.
2) Absence of the DIAPH3 mutation in a screen amongst 128 normal controls.
3) Highly specific expression of DIAPH3 in the developing cortex of the mouse during embryogenesis.
4) Available literature suggests that DIAPH3 is a central gene in the actin polymerization pathway, which is an essential mechanism for neuronal migration.
Conclusions: DIAPH3 is a relevant candidate gene for autism.