A double hit implicates DIAPH3 as an autism risk gene

Abstract

Recent studies have shown 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 function 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 nonsynonymous amino-acid substitution at position 614 of diaphanous homolog 3 (DIAPH3) (proline to threonine; Pro614Thr). This variant, present in a highly conserved domain, was not found in 328 healthy subjects. Experiments showed a transient expression of Diaph3 in the developing murine cerebral cortex, indicating it has a function in brain development. Transfection of Pro614Thr in murine fibroblasts showed 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 shows 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.

Dendritic spine actin cytoskeleton in autism spectrum disorder

“…A maternally inherited deletion and a paternally inherited functional single-nucleotide mutation in a highly-conserved nucleotide sequence of DIAPH3 have been reported in a normally intelligent patient with an autistic disorder, suggesting a homozygous loss of function in the DRF3 82 . Rare genomic alterations in DIAPH3 have also been found in rare epileptic encephalopathies such as the continuous spike and waves during slow-wave sleep (CSWSS) syndrome and Landau-Kleffner syndrome (LKS) 83 .…”

Small-Molecule Intramimics of Formin Autoinhibition: A New Strategy to Target the Cytoskeletal Remodeling Machinery in Cancer Cells

“…These structural changes occur in response to demands during developmental and immunologic processes (2). Defects in formin genes are associated with an array of human diseases including inherited deafness, autism, and kidney disease (3,4).…”

Genetic Heterogeneity of Autism Spectrum Disorders

“…A deletion at a particular locus might also result in the unmasking of a recessive gene on the corresponding chromosomal locus, which would then be able to elicit a deleterious effect. Such a mechanism might be involved in disease pathogenesis in an autistic individual with a 10 Mb maternally inherited deletion in chromosome 13q and a point mutation in the DIAPH3 gene on the paternal chromosome (Vorstman et al, 2010). As the proband's unaffected sibling also had the DIAPH3 mutation, but lacked the corresponding deletion, it is tempting to argue that the maternal deletion unmasked a recessive mutation in the paternal DIAPH3 gene, and that in turn influenced the onset of ASD in the proband.…”