A large-scale survey of the novel 15q24 microdeletion syndrome in autism spectrum disorders identifies an atypical deletion that narrows the critical region

Seaver Autism Center for Research and Treatment, Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA. .
Molecular Autism (Impact Factor: 5.41). 03/2010; 1(1):5. DOI: 10.1186/2040-2392-1-5
Source: PubMed


The 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with intellectual disability, typical facial appearance, hypotonia, and digital and genital abnormalities. Gene dosage abnormalities, including copy number variations (CNVs), have been identified in a significant fraction of individuals with autism spectrum disorders (ASDs). In this study we surveyed two ASD cohorts for 15q24 abnormalities to assess the frequency of genomic imbalances in this interval.
We screened 173 unrelated subjects with ASD from the Central Valley of Costa Rica and 1336 subjects with ASD from 785 independent families registered with the Autism Genetic Resource Exchange (AGRE) for CNVs across 15q24 using oligonucleotide arrays. Rearrangements were confirmed by array comparative genomic hybridization and quantitative PCR.
Among the patients from Costa Rica, an atypical de novo deletion of 3.06 Mb in 15q23-q24.1 was detected in a boy with autism sharing many features with the other 13 subjects with the 15q24 microdeletion syndrome described to date. He exhibited intellectual disability, constant smiling, characteristic facial features (high anterior hairline, broad medial eyebrows, epicanthal folds, hypertelorism, full lower lip and protuberant, posteriorly rotated ears), single palmar crease, toe syndactyly and congenital nystagmus. The deletion breakpoints are atypical and lie outside previously characterized low copy repeats (69,838-72,897 Mb). Genotyping data revealed that the deletion had occurred in the paternal chromosome. Among the AGRE families, no large 15q24 deletions were observed.
From the current and previous studies, deletions in the 15q24 region represent rare causes of ASDs with an estimated frequency of 0.1 to 0.2% in individuals ascertained for ASDs, although the proportion might be higher in sporadic cases. These rates compare with a frequency of about 0.3% in patients ascertained for unexplained intellectual disability and congenital anomalies. This atypical deletion reduces the minimal interval for the syndrome from 1.75 Mb to 766 kb, implicating a reduced number of genes (15 versus 38). Sequencing of genes in the 15q24 interval in large ASD and intellectual disability samples may identify mutations of etiologic importance in the development of these disorders.

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    • "Phenotypic features include mild to moderate developmental delay, characteristic facial features, growth retardation, hypotonia, joint laxity, digital abnormalities and genital abnormalities. Smith et al. in 2008 also described a girl (previously been assessed by FISH24) with autism, developmental delay and mild dysmorphism containing a 15q24 deletion overlapping the genomic region identified by Sharp et al. (Moyra Smith, personal communication), which has already been reported and is associated with intellectual disability and autism.[25] "
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    • "Further analyses will be needed to demonstrate the underlying mechanism by which this SNP might influence the inter-individual variations in sensitivity to the effect of low-dose BPA and increased risk of HS. It is known that ARNT2 is located on 15q24-25, while 15q24 microdeletion syndrome has been recently described as a recurrent, submicroscopic genomic imbalance found in individuals with developmental delay, craniofacial dysmorphism, digital and genital abnormalities (including HS) [30], [31], [32]. Other possible interpretations of our findings include the interactions between genetic loci located on 15q24-25, although further study is necessary to investigate this possibility. "
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    • "Behavior abnormalities, such as autism, hyperactivity, aggression, and attention deficit disorder have been reported in 37% individuals with 15q24 deletion syndrome. McInnes et al performed targeted aCGH across the 15q24 region on ~1500 individuals with autism spectrum disorders and identified a de novo atypical deletion of 3.06 Mb in 15q23-q24.1 in a 5 year old male with autism [8]. In addition to autism, he exhibited other characteristic features of 15q24 deletion syndrome including, moderate intellectual disability, low birth weight, distinct facial features, 2,3 toe syndactyly, mild scoliosis, and recurrent respiratory infections. "
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