A new candidate gene for autism suggested by the co-occurrence of a deletion and a mutation in a child with autism

Background: despite the fact that the heritability of autism is thought to be high, replication of genetic linkage and association findings across different studies has been difficult. An alternative to linkage type studies is the analysis of (cyto)genetic abnormalities that co-occur with the autism phenotype, under the assumption of a causal relationship between the genetic abnormality and the autistic phenotype. In some cases, a deletion may "reveal" a recessive variation on the non-deleted allele.

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.

Results:

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.