title: Does parent of origin matter? Methylation studies should be performed on patients with multiple copies of the Prader-Willi/Angelman syndrome critical region.
abstract: Deletion of 15q11.2-q13 results in either Prader-Willi syndrome (PWS) or Angelman syndrome (AS) depending on the parent of origin. Duplication of the PWS/AS critical region (PWASCR) has also been reported in association with developmental delay and autism, and it has been shown that they also show a parent-of-origin effect. It is generally accepted that maternal duplications are pathogenic. However, there is conflicting evidence as to the pathogenicity of paternal duplications. We have identified 35 patients with gain of the PWASCR using array comparative genomic hybridization. Methylation testing was performed to determine parent of origin of the extra copies. Of the 35 cases, 22 had a supernumerary marker chromosome 15 (SMC15), 12 had a tandem duplication, and 1 had a tandem triplication. Only one patient had a paternal duplication; this patient does not have features typical of patients with maternal duplication of the PWASCR. Three of the mothers had a tandem duplication (two were paternal and one was maternal origin). While one of the two mothers with paternal duplication was noted not to have autism, the other was noted to have learning disability and depression. Based on our data, we conclude that SMC15 are almost exclusively maternal in origin and result in an abnormal phenotype. Tandem duplications/triplications are generally of maternal origin when ascertained on the basis of abnormal phenotype; however, tandem duplications of paternal origin have also been identified. Therefore, we suggest that methylation testing be performed for cases of tandem duplications/triplications since the pathogenicity of paternal gains is uncertain.
authors: Cytogenetics Laboratory, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
authors: Umut
authors: U
authors: Aypar
authors: Pamela R
authors: PR
authors: Brodersen
authors: Patrick A
authors: PA
authors: Lundquist
authors: D Brian
authors: DB
authors: Dawson
authors: Erik C
authors: EC
authors: Thorland
authors: Nicole
authors: N
authors: Hoppman
mesh_terms: D000293:Adolescent; D000328:Adult; D017204:Angelman Syndrome / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D058674:Chromosome Duplication / Q000235:genetics; D002884:Chromosomes, Human, Pair 15 / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D002658:Developmental Disabilities / Q000235:genetics; D005260:Female; D018628:Gene Dosage / Q000235:genetics*; D020440:Gene Duplication / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D010290:Parents; D010641:Phenotype; D011218:Prader-Willi Syndrome / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics; D055815:Young Adult
keywords: 15q11.2-q13; MS-MLPA; PWASCR; array CGH; autism