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

Abstract

BackgroundThe 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.MethodsWe 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.ResultsThe 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.ConclusionsWe 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.

Association of congenital cardiovascular malformation and neuropsychiatric phenotypes with 15q11.2 (BP1–BP2) deletion in the UK Biobank

“…We confirmed the association of the deletion with CVM (OR = 1.73 [95% CI 1.08-2.75]; p = 0.03) and, in broad agreement with recent findings from others [17], with neuropsychiatric disorders (OR = 1.84 [95% CI 1.23-2.75]; p = 0.0043), measures of cognitive function, academic achievement and fecundity. We confirmed the association of BP1-BP2 deletion with CVM, which has been observed in some but not all previous studies [25][26][27]36]. The first study linking BP1-BP2 deletions with non-syndromic CVM showed an odds ratio of 8.2 [95% CI 1.06-62.98]; the point estimate for the risk associated with the deletion was much less in this study, but still falling within the 95% confidence interval of the estimate from the first study.…”

“…Regarding the classification of the deletion for the purposes of clinical genetics and genetic counselling, we tend to agree with Jønch et al that the deletion should be classified as "pathogenic, of mild effect size" [36]. The effect on CVM is not sufficient to justify genetic testing in children presenting with CVM as their primary diagnosis, and our conclusions regarding neuropsychiatric manifestations of the deletion are in agreement both with that previous study, and others in the UKB cohort [17].…”

“…A recent meta-analysis of phenotypic associations of the 15q11.2 deletion substituted the prevalence of the deletion in UKB healthy controls of 0.36% for the prevalences actually observed in previous studies of CVM, and concluded that there was no evidence for enrichment for the deletion in CVM cases [36]. We suggest that such betweenstudy comparison of prevalences determined on different assay platforms may not be straightforward to interpret.…”

Should We Report 15q11.2 BP1-BP2 Deletions and Duplications in the Prenatal Setting?

“…Most of the CNVs in this region are inherited either maternally or paternally [3,11]. Deletions were reported in individuals with developmental delay, motor and speech impairments, schizophrenia, epilepsy, behavioral problems, attention deficit hyperactivity disorder (ADHD), obsessive-compulsive behavior, dysmorphism, malformations and an unusually happy expression [11][12][13][14][15][16][17]. Unaffected carriers were reported to have decreased cognitive abilities and general measures of functioning [18].…”

Analysis of diffusion tensor imaging data from UK Biobank confirms dosage effect of 15q11.2 copy-number variation on white matter and shows association with cognition

“…In this study, we compared carriers to thousands of controls, which provides a better estimate of the general population mean, and therefore a more reliable estimate of effect sizes (57). The deletion has been proposed as a pathogenic CNV of mild effect size (58), which is in line with the smaller effect sizes found in the UK Biobank data. In the Icelandic sample, carriers were compared to 19 NoCNV controls, which may have led to an overestimation of the CNV effect.…”