A paternally inherited duplication in the Prader-Willi/Angelman syndrome critical region: A case and family study

Developmental Psychiatry Section, University of Cambridge, Cambridge, UK.
Journal of Autism and Developmental Disorders (Impact Factor: 3.34). 03/2005; 35(1):117-27. DOI: 10.1007/s10803-004-1039-1
Source: PubMed

ABSTRACT The Prader-Willi/Angelman Critical Region (PWACR; Chromosome 15q11-13) is of interest as a potential locus for genes conferring susceptibility to autism spectrum disorders (ASD). This report describes a female proband referred for evaluation of a possible ASD. Genetic analyses indicated that the proband, her father and one of her sisters, carried a paternally derived interstitial duplication involving 15q11-13. The proband showed evidence of ASD (PDD-NOS), borderline mental retardation, mild hypotonia and joint laxity. Her father and her sister were of normal intelligence and neither was thought to have an ASD, although speech/language difficulties and some autistic type behaviours were reported to have been present early in the development of the sister. This is one of the first reports of a child with a paternal duplication and an autism spectrum disorder. More research is required to determine whether paternally derived duplications that involve 15q11-13 are associated with developmental impairments.

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    ABSTRACT: Background: It has been estimated that as many as ~3-5% of all autism cases may be the result of duplications of the 15q11-q13 region. Unfortunately, genotype-phenotype correlations have not consistently demonstrated that these duplications are the sole cause of ASD in these cases. Maternally transmitted 15q duplications consistently show autistic features with variable degrees of developmental delay. Only a few cases of paternally transmitted 15q duplication have been reported and are associated with speech delay and behavior problems, but not autism. Objectives: to perform an in depth phenotype analysis of individuals with interstitial 15q duplications and determine if maternal duplication is required for the diagnosis of autism spectrum disorder (ASD Methods: We used neuropsychological, language and ASD diagnostic tools for phenotypic analysis in patients recruited through the IDEAS parent support group ( In addition we performed High Resolution Melting analysis (HRM) of the maternally methylated SNRPN locus to determine the parent of origin of the duplications Results: Nine pediatric subjects with interstitial duplication 15q have participated in the study. Eight patients scored as ASD upon ADOS/ADI-R analysis and one scored “no ASD” on both tests. In the neuropsychological evaluations 3/9 patients had a low average IQ score, 3/9 were borderline and the others had mental retardation, although the patients were noted to have a higher verbal IQ than performance, they had a low-moderate adaptive functioning score on the Vineland II evaluation. All patients performed below age corrected average for receptive vocabulary (Peabody Picture vocabulary test). HRM analysis was done in all patients: 8/9 had a maternal duplication and 1/9 had a paternal duplication. The sizes of the duplications ranged from 5Mb to 12.77Mb and included typical BP1-BP3, BP2-BP3 and duplications including the BP1-BP3 region plus additional regions upstream or downstream of the BP1-BP3 region. The size of the duplication involved does not appear to correlate with the severity of the phenotype or the ASD diagnosis. Conclusions: in our study only maternally derived interstitial duplications result in ASD, not paternal duplications. It should be noted that several of our patients were adopted so parental DNA was unavailable for genotype analysis. HRM analysis for maternal specific methylation patterns at the SNRPN locus allowed us to determine the parental origin of the duplication in all samples tested.
    International Meeting for Autism Research 2010; 05/2010
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    ABSTRACT: Paternally and maternally inherited deletions and duplications of human chromosome 15q11-13 are relatively common in the human population. Furthermore, duplications in the 15q region are often associated with autism. Both maternal and paternal interstitial 15q11-13 duplication mouse models have been previously created, where several behavioral differences were found in the paternal duplication (patDp/+) mouse but not in the maternal duplication (matDp/+). These included decreased sociability, behavioral inflexibility, abnormal ultrasonic vocalizations, decreased spontaneous activity, and increased anxiety. Similarly, in the current study, we found several anatomical differences in the patDp/+ mice that were not seen in the matDp/+ mice. Regional differences that are evident only in the paternal duplication are a smaller dentate gyrus and smaller medial striatum. These differences may be responsible for the behavioral inflexibility. Furthermore, a smaller dorsal raphe nucleus could be responsible for the reported serotonin defects. This study highlights consistency that can be found between behavioral and anatomical phenotyping. Autism Res 2015. © 2015 International Society for Autism Research, Wiley Periodicals, Inc. © 2015 International Society for Autism Research, Wiley Periodicals, Inc.
    Autism Research 03/2015; DOI:10.1002/aur.1469 · 4.53 Impact Factor
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    ABSTRACT: Autism is a neurodevelopmental disorder that manifests in childhood as social behavioral abnormalities, such as abnormal social interaction, impaired communication, and restricted interest or behavior. Of the known causes of autism, duplication of human chromosome 15q11-q13 is the most frequently associated cytogenetic abnormality. Chromosome 15q11-q13 is also known to include imprinting genes. In terms of neuroscience, it contains interesting genes such as Necdin, Ube3a, and a cluster of GABA(A) subunits as well as huge clusters of non-coding RNAs (small nucleolar RNAs, snoRNAs). Phenotypic analyses of mice genetically or chromosomally engineered for each gene or their clusters on a region of mouse chromosome seven syntenic to human 15q11-q13 indicate that this region may be involved in social behavior, serotonin metabolism, and weight control. Further studies using these models will provide important clues to the pathophysiology of autism. This review overviews phenotypes of mouse models of genes in 15q11-q13 and their relationships to autism.
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