A double hit implicates DIAPH3 as an autism risk gene

Department of Psychiatry, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Utrecht, The Netherlands.
Molecular Psychiatry (Impact Factor: 14.5). 03/2010; 16(4):442-51. DOI: 10.1038/mp.2010.26
Source: PubMed


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.

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    • "A first hypothesis to explain this phenotypic heterogeneity is that a secondary insult is necessary during development to result in the phenotype, as in the “twohit model” proposed in developmental delay.48 Several studies recently supported the existence of such a combination of rare variants in some cases.39,49,50 Another hypothesis is the contribution of both rare and frequent variants. "
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    • "A recent study has identified DIAPH3 as a new autism susceptibility gene by virtue of rare non-synonymous variants lying in trans with a deletion.41 The sharing of non-deleted paternal CDH8 haplotypes in the three affected siblings in family 3099 made us consider the possibility that this 1.64 Mb deletion was also unmasking rare variants in the remaining copy of CDH8. "
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