Estimating the effect size of the 15Q11.2 BP1-BP2 deletion and its contribution to neurodevelopmental symptoms: recommendations for practice

Abstract

Background: The 15q11.2 deletion is frequently identified in the neurodevelopmental clinic. Case-control studies have associated the 15q11.2 deletion with neurodevelopmental disorders, and clinical case series have attempted to delineate a microdeletion syndrome with considerable phenotypic variability. The literature on this deletion is extensive and confusing, which is a challenge for genetic counselling. The aim of this study was to estimate the effect size of the 15q11.2 deletion and quantify its contribution to neurodevelopmental disorders.

Methods: We performed meta-analyses on new and previously published case-control studies and used statistical models trained in unselected populations with cognitive assessments. We used new (n=241) and previously published (n=150) data from a clinically referred group of deletion carriers. 15q11.2 duplications (new n=179 and previously published n=35) were used as a neutral control variant.

Results: The deletion decreases IQ by 4.3 points. The estimated ORs and respective frequencies in deletion carriers for intellectual disabilities, schizophrenia and epilepsy are 1.7 (3.4%), 1.5 (2%) and 3.1 (2.1%), respectively. There is no increased risk for heart malformations and autism. In the clinically referred group, the frequency and nature of symptoms in deletions are not different from those observed in carriers of the 15q11.2 duplication suggesting that most of the reported symptoms are due to ascertainment bias.

Conclusions: We recommend that the deletion should be classified as 'pathogenic of mild effect size'. Since it explains only a small proportion of the phenotypic variance in carriers, it is not worth discussing in the developmental clinic or in a prenatal setting.

Keywords: 15q11.2 copy-number variants; congenital heart disease; epilepsy; loss-of-function intolerance; neurodevelopmental disorders.

Figure 1

The 15q11.2 deletion case–control studies of neurodevelopmental disorders and CHD. Forest plot showing the results of 20 studies including the SJCHU and OUH cohorts examining the association between the 15q11.2 deletion and the OR of a neurodevelopmental disorder or CHD in cases versus controls. Of note, the year reported for the SJCHU and OUH cohorts refers to the year the data were extracted and analysed. Previously published studies are detailed in the online supplementary table S1. If a study contains a value of zero, we added 0.5 as suggested by the rma function of the metafor package. Data in the individual studies are reported with corresponding 95% CI based on a RE model. The horizontal whiskers correspond to the 95% CI for each study. The sizes of the box areas are proportional to the weight of the individual study in the meta-analysis. The width of the diamond is a summary estimate of the CI, and the dotted vertical line shows the null value of the OR and is equivalent to no effect. OR in the left side shows the OR and 95% CI for studies including the original control population, and OR in the right side shows the OR and 95% CI for the recomputed studies with the UK BIOBANK as control population (n=151 619). The test for heterogeneity (Q=39.74, df=19, p=0.00, I²=61.5%) for OR (left side) using the original control population suggests important heterogeneity among the studies. The I² statistic describes the percentage (0%–100%) of total variation across studies that is due to heterogeneity rather than chance. The 0% indicate no observed heterogeneity, while larger values show increasing heterogeneity. Publication bias was assessed in a funnel plot (online supplementary figure S2), and the Egger’s test was used to test for funnel plot asymmetry (z=2.1337, p=0.0329). A p value below 0.05 suggests the presence of publication bias in the funnel plot. ASD, autism spectrum disorders; CHD, congenital heart disease; del+, cases or controls with the 15q11.2 deletion, del−, cases or controls without the 15q11.2 deletion; DD/ID, developmental delay/intellectual disability; df, number of studies; OUH, Odense University Hospital; Q, χ² test of heterogeneity; RE, random effect; SJCHU, Saint-Justine University Hospital; SZ, schizophrenia.

Figure 2

The 15q11.2 duplication case–control studies of neurodevelopmental disorders. Forest plot showing the results of seven studies including the SJCHU and OUH cohorts examining the association between the 15q11.2 duplication and the OR of a neurodevelopmental disorder in cases versus controls. Of note, the year reported for the SJCHU and OUH cohorts refers to the year the data were extracted and analysed. Published studies are detailed in the online supplementary table S2. Data in the individual studies are reported with corresponding 95% CI based on a RE model. The test for heterogeneity (Q=16.41, df=6, p=0.01, I²=67.6%) for OR (left side) using the original control population suggests important heterogeneity among the studies. Publication bias was assessed in a funnel plot (online supplementary figure S3) and the Egger’s test was used to test for funnel plot asymmetry (z=3.3826, p=0.0007). This result suggests asymmetry in the funnel plot, and the presence of publication bias. ASD, autism spectrum disorders; dup+, cases or controls with the duplication; dup−, cases or controls without the duplication; DD/ID, developmental delay/intellectual disability; df, number of studies; OUH, Odense University Hospital; Q, X² test of heterogeneity; RE, random effect; SJCHU, Saint-Justine University Hospital. See figure 1 legend for more details.