TY  - JOUR
A1  - Isles, Anthony R.
A1  - Ingason, Andrés
A1  - Lowther, Chelsea
A1  - Walters, James
A1  - Gawlick, Micha
A1  - Stöber, Gerald
A1  - Rees, Elliott
A1  - Martin, Joanna
A1  - Little, Rosie B.
A1  - Potter, Harry
A1  - Georgieva, Lyudmila
A1  - Pizzo, Lucilla
A1  - Ozaki, Norio
A1  - Aleksic, Branko
A1  - Kushima, Itaru
A1  - Ikeda, Masashi
A1  - Iwata, Nakao
A1  - Levinson, Douglas F.
A1  - Gejman, Pablo V.
A1  - Shi, Jianxin
A1  - Sanders, Alan R.
A1  - Duan, Jubao
A1  - Willis, Joseph
A1  - Sisodiya, Sanjay
A1  - Costain, Gregory
A1  - Werge, Thomas M.
A1  - Degenhardt, Franziska
A1  - Giegling, Ina
A1  - Rujescu, Dan
A1  - Hreidarsson, Stefan J.
A1  - Saemundsen, Evald
A1  - Ahn, Joo Wook
A1  - Ogilvie, Caroline
A1  - Girirajan, Santhosh D.
A1  - Stefansson, Hreinn
A1  - Stefansson, Kari
A1  - O'Donovan, Michael C.
A1  - Owen, Michael J.
A1  - Bassett, Anne
A1  - Kirov, George
T1  - Parental Origin of Interstitial Duplications at 15q11.2-q13.3 in Schizophrenia and Neurodevelopmental Disorders
JF  - PLoS Genetics
N2  - 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.
KW  - interstitial duplications
KW  - schizophrenia
KW  - developmental delay
KW  - autism spectrum disorder
KW  - parental origin
KW  - genetics
Y1  - 2016
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-166706
VL  - 12
IS  - 5
ER  -