Non-recurrent Copy Number Variants Research Articles

Measuring and Estimating the Effect Sizes of Copy Number Variants on General Intelligence in Community-Based Samples

Copy number variants (CNVs) classified as pathogenic are identified in 10% to 15% of patients referred for neurodevelopmental disorders. However, their effect sizes on cognitive traits measured as a continuum remain mostly unknown because most of them are too rare to be studied individually using association studies. To measure and estimate the effect sizes of recurrent and nonrecurrent CNVs on IQ. This study identified all CNVs that were 50 kilobases (kb) or larger in 2 general population cohorts (the IMAGEN project and the Saguenay Youth Study) with measures of IQ. Linear regressions, including functional annotations of genes included in CNVs, were used to identify features to explain their association with IQ. Validation was performed using intraclass correlation that compared IQ estimated by the model with empirical data. Performance IQ (PIQ), verbal IQ (VIQ), and frequency of de novo CNV events. The study included 2090 European adolescents from the IMAGEN study and 1983 children and parents from the Saguenay Youth Study. Of these, genotyping was performed on 1804 individuals from IMAGEN and 977 adolescents, 445 mothers, and 448 fathers (484 families) from the Saguenay Youth Study. We observed 4928 autosomal CNVs larger than 50 kb across both cohorts. For rare deletions, size, number of genes, and exons affect IQ, and each deleted gene is associated with a mean (SE) decrease in PIQ of 0.67 (0.19) points (P = 6 × 10-4); this is not so for rare duplications and frequent CNVs. Among 10 functional annotations, haploinsufficiency scores best explain the association of any deletions with PIQ with a mean (SE) decrease of 2.74 (0.68) points per unit of the probability of being loss-of-function intolerant (P = 8 × 10-5). Results are consistent across cohorts and unaffected by sensitivity analyses removing pathogenic CNVs. There is a 0.75 concordance (95% CI, 0.39-0.91) between the effect size on IQ estimated by our model and IQ loss calculated in previous studies of 15 recurrent CNVs. There is a close association between effect size on IQ and the frequency at which deletions occur de novo (odds ratio, 0.86; 95% CI, 0.84-0.87; P = 2.7 × 10-88). There is a 0.76 concordance (95% CI, 0.41-0.91) between de novo frequency estimated by the model and calculated using data from the DECIPHER database. Models trained on nonpathogenic deletions in the general population reliably estimate the effect size of pathogenic deletions and suggest omnigenic associations of haploinsufficiency with IQ. This represents a new framework to study variants too rare to perform individual association studies and can help estimate the cognitive effect of undocumented deletions in the neurodevelopmental clinic.

Clinical relevance of small copy-number variants in chromosomal microarray clinical testing.

The 2010 consensus statement on diagnostic chromosomal microarray (CMA) testing recommended an array resolution ≥400 kb throughout the genome as a balance of analytical and clinical sensitivity. In spite of the clear evidence for pathogenicity of large copy-number variants (CNVs) in neurodevelopmental disorders and/or congenital anomalies, the significance of small, nonrecurrent CNVs (<500 kb) has not been well established in a clinical setting. We investigated the clinical significance of all nonpolymorphic small, nonrecurrent CNVs (<500 kb) in patients referred for CMA clinical testing over a period of 6 years, from 2009 to 2014 (a total of 4,417 patients). We excluded from our study patients with benign or likely benign CNVs and patients with only recurrent microdeletions/microduplications <500 kb. In total, 383 patients (8.67%) were found to carry at least one small, nonrecurrent CNV, of whom 176 patients (3.98%) had one small CNV classified as a variant of uncertain significance (VUS), 45 (1.02%) had two or more small VUS CNVs, 20 (0.45%) had one small VUS CNV and a recurrent CNV, 113 (2.56%) had one small pathogenic or likely pathogenic CNV, 17 (0.38%) had two or more small pathogenic or likely pathogenic CNVs, and 12 (0.27%) had one small pathogenic or likely pathogenic CNV and a recurrent CNV. Within the pathogenic group, 80 of 142 patients (56% of all small pathogenic CNV cases) were found to have a single whole-gene or exonic deletion. The themes that emerged from our study are presented in the Discussion section. Our study demonstrates the diagnostic clinical relevance of small, nonrecurrent CNVs <500 kb during CMA clinical testing and underscores the need for careful clinical interpretation of these CNVs.Genet Med 19 4, 377-385.

Genome-wide Transcriptome Profiling Reveals the Functional Impact of Rare De Novo and Recurrent CNVs in Autism Spectrum Disorders

Copy-number variants (CNVs) are a major contributor to the pathophysiology of autism spectrum disorders (ASDs), but the functional impact of CNVs remains largely unexplored. Because brain tissue is not available from most samples, we interrogated gene expression in lymphoblasts from 244 families with discordant siblings in the Simons Simplex Collection in order to identify potentially pathogenic variation. Our results reveal that the overall frequency of significantly misexpressed genes (which we refer to here as outliers) identified in probands and unaffected siblings does not differ. However, in probands, but not their unaffected siblings, the group of outlier genes is significantly enriched in neural-related pathways, including neuropeptide signaling, synaptogenesis, and cell adhesion. We demonstrate that outlier genes cluster within the most pathogenic CNVs (rare de novo CNVs) and can be used for the prioritization of rare CNVs of potentially unknown significance. Several nonrecurrent CNVs with significant gene-expression alterations are identified (these include deletions in chromosomal regions 3q27, 3p13, and 3p26 and duplications at 2p15), suggesting that these are potential candidate ASD loci. In addition, we identify distinct expression changes in 16p11.2 microdeletions, 16p11.2 microduplications, and 7q11.23 duplications, and we show that specific genes within the 16p CNV interval correlate with differences in head circumference, an ASD-relevant phenotype. This study provides evidence that pathogenic structural variants have a functional impact via transcriptome alterations in ASDs at a genome-wide level and demonstrates the utility of integrating gene expression with mutation data for the prioritization of genes disrupted by potentially pathogenic mutations.