A double hit implicates DIAPH3 as an autism risk gene.
Résumé
Recent studies have demonstrated that more than 10% of autism cases are caused by de novo structural genomic rearrangements. Given that some heritable copy number variants (CNVs) have been observed in patients as well as in healthy controls, to date little attention has been paid to the potential role of these non-de novo CNVs in causing autism. A normally intelligent patient with autism, with non-affected parents, was identified with a maternally inherited 10 Mb deletion at 13q21.2. Sequencing of the genes within the deletion identified a paternally inherited non-synonymous amino acid substitution at position 614 of DIAPH3 (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments demonstrated a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it plays a role in brain development. Transfection of Pro614Thr in murine fibroblasts demonstrated a significant reduction in the number of induced filopodia in comparison to the wild-type gene. DIAPH3 is involved in cell migration, axon guidance and neuritogenesis, and is suggested to function downstream of SHANK3. Our findings strongly suggest DIAPH3 as a novel autism susceptibility gene. Moreover, this report of a "double hit" compound heterozygote for a large, maternally inherited, genomic deletion and a paternally inherited rare missense mutation illustrates that not only de novo genomic variants in patients should be taken seriously in further study but that inherited CNVs may also provide valuable information.
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