Abstract
The most common chromosomal abnormalities associated with autism are 15q11-q13 duplications. Maternally derived or inherited duplications of 15q pose a substantial risk for an autism phenotype, while paternally derived duplications may be incompletely penetrant or result in other neurodevelopmental problems. Therefore, the determination of maternal versus paternal origin of this duplication is important for early intervention therapies and for appropriate genetic counseling to the families. We adapted a previous single-reaction tube assay (high-resolution melting curve analysis) to determine the parent of origin of 15q duplications in 28 interstitial duplication 15q samples, one family and two isodicentric subjects. Our method distinguished parent origin in 92% of the independent samples as well as in the familial inherited duplication and in the two isodicentric samples. This method accurately determines parental origin of the duplicated segment and measures the dosage of these alleles in the sample. In addition, it can be performed on samples where parental DNA is not available for microsatellite analysis. The development of this single-tube assay will make it easier for genetic testing laboratories to provide parent-of-origin information and will provide important information to clinical geneticists about autism risk in these individuals.
Highlights
The most common chromosomal abnormalities associated with autism are duplications of the proximal region of chromosome 15q encompassing the imprinted Prader-Willi/ Angelman syndrome (PWS/AS) locus
The basis of our methylation-sensitive high-resolution melting (HRM) curve assay is a study by White et al (2007) demonstrating that in the case of either deletion or uniparental disomy (UPD) for the SNRPN gene, it would be possible to determine the parent of origin of the remaining homoallelic region using a primer set that amplifies the bisulfite-converted residues resulting in a single but distinct melting curve for AS and PWS
In the era of high-resolution whole-genome oligonucleotide arrayCGH, there is no question that the detection of chromosome 15q duplications encompassing the PWS/AS locus combined with confirmation by fluorescence in situ hybridization (FISH) analysis has become standard practice in the genetics clinic for the investigation of autism spectrum disorder (ASD) phenotypes
Summary
The most common chromosomal abnormalities associated with autism are duplications of the proximal region of chromosome 15q encompassing the imprinted Prader-Willi/ Angelman syndrome (PWS/AS) locus. In PWS and AS, assays are available to identify the methylation state of the deleted chromosome; it is frequently not feasible to clearly determine parent of origin for patients with duplication using molecular assays available clinically. This is an important limitation to the current methodologies because there is tremendous variation in phenotypic risks for individuals with maternal versus paternal chromosome 15q duplications. The determination of maternal versus paternal imprinting status of this duplication is clinically important in terms of both early intervention therapies for autism and for appropriate genetic counseling of unaffected individuals who may carry a paternally derived or inherited 15q interstitial duplication
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