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

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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Family trees depicting transmission of 15q11.2-q13.3 duplications and neuropsychiatric phenotypes.

<p>Red fill indicates maternal duplications, blue indicates paternal duplications, and grey indicates no duplications. Samples where no DNA was available have no fill. Where DNA samples were available, parent of origin was determined using methylation-sensitive high-resolution melt curve analysis, or methylation-sensitive Southern Blot. Neuropsychiatric phenotype (detailed in <a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005993#pgen.1005993.s004" target="_blank">S1 Table</a>) is indicated as follows: SZ—schizophrenia; SZA—schizoaffective; DD—developmental delay; UA—unaffected. In addition, one individual was reported to have epilepsy and another ADHD.</p

Prevalence of 15q11-q13 duplications in disease and control cohorts.

<p>Prevalence of 15q11-q13 duplications in disease and control cohorts.</p

Penetrance estimates for the 15q11.2-q13.3 duplication.

<p>In brackets are shown the 95%CI, calculated with the methods described in [<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005993#pgen.1005993.ref024" target="_blank">24</a>].</p

Selection coefficient estimates for 15q11.2-q13.3 duplications.

<p>Selection coefficients are approximated as the proportion of <i>de novo</i> CNV out of the total number of CNVs: <i>de novo</i>/(<i>de novo</i> + inherited).</p

CNVs on chromosome 15.

<p>The image depicts the region on chromosome 15 that is affected by deletions and duplications caused by a number of low copy repeats. These form five recognised breakpoints (BPs) which cause the formation of deletions and duplications of different sizes. Several of them result in recognised syndromes: PWS/AS, 15q11.2 deletion and 15q13.3 deletion and duplication. The black bars at the top show the positions of the SZ/SZA probands in the current study (<a href="http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.1005993#pgen.1005993.s004" target="_blank">S1 Table</a>). All four combinations of duplications between BP1 and BP4 are represented. They all intersect the regions of maternally and paternally expressed genes and the GABA receptors gene cluster.</p