Position effect leading to haploinsufficiency in a mosaic ring chromosome 14 in a boy with autism

Abstract

We describe an individual with autism and a coloboma of the eye carrying a mosaicism for a ring chromosome consisting of an inverted duplication of proximal chromosome 14. Of interest, the ring formation was associated with silencing of the amisyn gene present in two copies on the ring chromosome and located at 300 kb from the breakpoint. This observation lends further support for a locus for autism on proximal chromosome 14. Moreover, this case suggests that position effects need to be taken into account, when analyzing genotype -phenotype correlations based on chromosomal imbalances.

The Autism Candidate Gene Neurobeachin Encodes a Scaffolding Protein Implicated in Membrane Trafficking and Signaling

“…Compared to patients with normal chromosome 13, there was a decrease in NBEA expression level in patients with a chromosome 13 deletion indicating that NBEA may be a new tumor suppressor gene for MM. Some other patients with del [13] show a very high NBEA expression [38,92]. Pharmacological inhibition of the Notch pathway prevents drug resistance and sensitizes the myeloma cells to chemotherapy [93].…”

“…The identified candidate regions also encompass too many genes to be able to identify the causal genes. In an alternative approach, candidate genes have been identified by mutation analysis or positional cloning of genes located at or in the neighborhood of a chromosomal breakpoint [3,4,[11][12][13][14]. Recently, genome-wide association studies have been performed resulting in a large number of potentially important novel candidate loci [15][16][17].…”

What’s new in autism?

“…A limitation of candidate gene association studies is that they require pre-existing hypotheses about the involved neurobiological systems, and these are very limited in ASD [119]. Other research methods include studying subjects with ASD associated with a single gene disorder or with a unique chromosomal defect affecting only one gene [1,[26][27][28][29]. In these genetically relatively simple models, molecular biology has already thrown some light on pathways involved in autism [102].…”

A three-step workflow procedure for the interpretation of array-based comparative genome hybridization results in patients with idiopathic mental retardation and congenital anomalies

“…[55][56][57] As has been shown recently in patients with Williams-Beuren syndrome, deletions may influence expression levels of the adjacent, nondeleted genes. 58 Recently, Castermans et al 59 showed that the AMYSIN gene located at 300 kb from a breakpoint of a ring 14 became silenced and this may account for the autistic phenotype of the patient. These examples indicate that other mechanisms than mere gene copy number alteration, such as gene silencing, may be involved in determining clinical phenotypes and therefore should be taken into account during interpretation of results from array-based aneuploidy profiling.…”