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PLoS Genet. 2016 May 6;12(5):e1005993. doi: 10.1371/journal.pgen.1005993. eCollection 2016 May.

Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders.

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Cardiff University, MRC Centre for Neuropsychiatric Genetics and Genomics, Institute of Psychological Medicine and Clinical Neurosciences, Cardiff University, Cardiff, United Kingdom.
DeCode Genetics, Reykjavik, Iceland.
Clinical Genetics Research Program, Centre for Addiction & Mental Health, University of Toronto, Toronto, Ontario, Canada.
University of Würzburg, Würzburg, Germany.
Oxford Gene Technology, Begbroke, Oxfordshire, United Kingdom.
Department of Biochemistry and Molecular Biology and Department of Anthropology, University Park, Pennsylvania, United States of America.
Department of Psychiatry, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya City, Aichi, Japan.
Department of Psychiatry, Fujita Health University School of Medicine, Toyoake, Aichi, Japan.
Department of Psychiatry, Stanford University, Palo Alto, California, United States of America.
Department of Psychiatry and Behavioral Sciences, Stanford University, Stanford, California, United States of America.
Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Medical Center Drive, Bethesda, Maryland, United States of America.
Department of Psychiatry and Behavioral Sciences, NorthShore University HealthSystem, Evanston, Illinois, United States of America; Department of Psychiatry and Behavioral Neuroscience, University of Chicago, Chicago, Illinois, United States of America.
UCL Institute of Neurology, Queen Square, London, United Kingdom.
Institute of Biological Psychiatry, Mental Health Centre Sct. Hans, Mental Health Services Copenhagen, University of Copenhagen, Copenhagen, Denmark.
Institute of Human Genetics, University of Bonn, Bonn, Germany.
Department of Psychiatry, University of Halle, Halle, Germany.
The State Diagnostic and Counselling Centre, Kópavogur, Iceland.
Faculty of Medicine, University of Iceland, Reykjavík, Iceland.
Guy's and St Thomas' NHS Foundation Trust, London, United Kingdom.


Duplications at 15q11.2-q13.3 overlapping the Prader-Willi/Angelman syndrome (PWS/AS) region have been associated with developmental delay (DD), autism spectrum disorder (ASD) and schizophrenia (SZ). Due to presence of imprinted genes within the region, the parental origin of these duplications may be key to the pathogenicity. Duplications of maternal origin are associated with disease, whereas the pathogenicity of paternal ones is unclear. To clarify the role of maternal and paternal duplications, we conducted the largest and most detailed study to date of parental origin of 15q11.2-q13.3 interstitial duplications in DD, ASD and SZ cohorts. We show, for the first time, that paternal duplications lead to an increased risk of developing DD/ASD/multiple congenital anomalies (MCA), but do not appear to increase risk for SZ. The importance of the epigenetic status of 15q11.2-q13.3 duplications was further underlined by analysis of a number of families, in which the duplication was paternally derived in the mother, who was unaffected, whereas her offspring, who inherited a maternally derived duplication, suffered from psychotic illness. Interestingly, the most consistent clinical characteristics of SZ patients with 15q11.2-q13.3 duplications were learning or developmental problems, found in 76% of carriers. Despite their lower pathogenicity, paternal duplications are less frequent in the general population with a general population prevalence of 0.0033% compared to 0.0069% for maternal duplications. This may be due to lower fecundity of male carriers and differential survival of embryos, something echoed in the findings that both types of duplications are de novo in just over 50% of cases. Isodicentric chromosome 15 (idic15) or interstitial triplications were not observed in SZ patients or in controls. Overall, this study refines the distinct roles of maternal and paternal interstitial duplications at 15q11.2-q13.3, underlining the critical importance of maternally expressed imprinted genes in the contribution of Copy Number Variants (CNVs) at this interval to the incidence of psychotic illness. This work will have tangible benefits for patients with 15q11.2-q13.3 duplications by aiding genetic counseling.

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