Screening for Genomic Rearrangements and Methylation Abnormalities of the 15q11-q13 Region in Autism Spectrum Disorders

Abstract

Our results show that abnormalities of the 15q11-q13 region are a significant cause of ASD, accounting for approximately 1% of cases. Maternal interstitial 15q11-q13 duplications, previously reported to be present in 1% of patients with ASD, were not detected in our sample. Although paternal duplications of chromosome 15 remain phenotypically silent in the majority of patients, they can give rise to developmental delay and ASD in some subjects, suggesting that paternally expressed genes in this region can contribute to ASD, albeit with reduced penetrance compared with maternal duplications. These findings indicate that patients with ASD should be routinely screened for 15q genomic imbalances and methylation abnormalities and that MLPA is a reliable, rapid, and cost-effective method to perform this screening.

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…However, duplications of paternal origin have occasionally been reported. 13,25 Our findings indicate that 15q11-q12 duplications and triplications of paternal origin might be less penetrant or associated with a milder phenotype than those of maternal origin. This suggests that dysregulation of both imprinted genes (including UBE3A) and non-imprinted genes in the 15q11-q13 region contribute to the development of ASDs.…”

“…Whole methylation analysis was performed for the subject with the 15q11-q12 triplication (8082), a patient with Angelman syndrome presenting with autistic features, previously reported, 13 and two young male controls by Integragen SA (Evry France). Bisulfite conversion of DNA was carried out to convert unmethylated cytosine nucleotides to uracil.…”

“…5,11,12 Several CNVs have been repeatedly identified in individuals with ASD, such as deletions or duplications on chromosomes 15q11-q13, 16p11.2, 7q11.23 and 22q13. 4,5,13 Private CNVs in individuals with autism often disrupt genes encoding synaptic proteins, such as neuroligins, neurexins and SHANK proteins, or neuronal cell-adhesion proteins, which have important roles in neurodevelopment and/or neurotransmission. 3,[14][15][16][17] However, most CNVs and variants in genes involved in autism so far are also found in other neurodevelopmental disorders such as ID without autistic features and/or schizophrenia.…”

Linkage and candidate gene studies of autism spectrum disorders in European populations

“…Assessment and selection criteria have been described previously for IMGSAC, 14 PARIS, 25 Finnish 12 and the Northern Dutch 22 probands. All affected individuals from the IMGSAC, PARIS and Northern Dutch cohorts had ADI-R 26 and/or ADOS 27 assessments.…”

Cross-Disorder Comparison of Four Neuropsychiatric CNV Loci

“…Both AS and PWS can also arise through other processes including: (1) Uniparental disomy of chromosome 15, in which two chromosomes are present (as normal), however, they both come from the same parent; (2) Small mutations that disrupt the imprinting center on 15q11.2; and (3) Small mutations in UBE3A on the maternal chromosome leading to AS [48,49] or in SNURF-SNRPN or snoRNAs on the paternal chromosome possibly leading to PWS [47,49]. Of note, no cases of AS or PWS were identified in the ASD cohort (Fig.…”