Unique de novo or X-linked maternally inherited CNVs are found in more than 10% of patients with syndromic ASD. (Jacquemont, 2006 and Qiao, 2009) These CNV regions are of unique value to ASD genetics because they may pinpoint to novel ASD candidate genes.
Objectives:
In this respect, we studied a unique discontiguous X-linked deletion on Xp11.22 in a boy with syndromic autism.
Methods:
We present genetic studies in a sporadic male patient with features reminiscent of Aarskog syndrome (caused by FGD1 mutations) and in addition cleft lip and palate and an ASD.
Results:
Molecular karyotyping with 1Mb resolution array-CGH revealed the presence of a maximally 4Mb microdeletion on Xp11.22, confirmed by FISH using the probe RP3-501A4. The deletion was inherited from the unaffected mother, who skews the mutated allele completely. However, fine mapping by means of an Agilent 244K array revealed the presence of two discontiguous deletions, confirmed by qPCR. A small intragenic deletion was detected in the FGD1 gene, explaining the Aarskog features. A second, centromeric deletion involved the PHF8 gene and part of the FAM120C gene. Mutations in PHF8 cause XLMR with cleft lip and/or palate. No autism has been described in these families. Of interest, Qiao et al. (2008) reported a family with autism segregating with an overlapping but larger microdeletion encompassing the FAM120C gene. This finding points towards the FAM120C gene as a novel positional X-linked candidate gene for autism. FAM120C belongs to a family of 3 relatively uncharacterized proteins with putative transmembrane domains, and shows enriched expression in human and mouse fetal brain. (Holden et al, 2003) Moreover, since its paralogue Fam120a (C9orf10) colocalizes with Fmrp at Puralpha-positive particles in the mouse hippocampus, FAM120C further represents a good biological candidate gene with regard to ASD. (Kobayashi, 2006)
Conclusions:
In a patient with a unique chromosomal rearrangement on Xp11.22, we identified FAM120C as a novel positional and biological ASD candidate gene. This study provides further support for the great value of unique rare variants in the understanding of ASD genetics. We will present the results of an ongoing mutation screen and additional expression studies in mice.