Genome-wide Analysis Of Copy Number Variants Research Articles

Germline copy number variants and endometrial cancer risk

Known risk loci for endometrial cancer explain approximately one third of familial endometrial cancer. However, the association of germline copy number variants (CNVs) with endometrial cancer risk remains relatively unknown. We conducted a genome-wide analysis of rare CNVs overlapping gene regions in 4115 endometrial cancer cases and 17,818 controls to identify functionally relevant variants associated with disease. We identified a 1.22-fold greater number of CNVs in DNA samples from cases compared to DNA samples from controls (p = 4.4 × 10–63). Under three models of putative CNV impact (deletion, duplication, and loss of function), genome-wide association studies identified 141 candidate gene loci associated (p < 0.01) with endometrial cancer risk. Pathway analysis of the candidate loci revealed an enrichment of genes involved in the 16p11.2 proximal deletion syndrome, driven by a large recurrent deletion (chr16:29,595,483-30,159,693) identified in 0.15% of endometrial cancer cases and 0.02% of control participants. Together, these data provide evidence that rare copy number variants have a role in endometrial cancer susceptibility and that the proximal 16p11.2 BP4-BP5 region contains 25 candidate risk gene(s) that warrant further analysis to better understand their role in human disease.

Genome-wide copy number variant analysis reveals candidate genes associated with milk production traits in water buffalo (Bubalus bubalis)

Buffaloes are vital contributors to the global dairy industry. Understanding the genetic basis of milk production traits in buffalo populations is essential for breeding programs and improving productivity. In this study, we conducted whole-genome resequencing on 387 buffalo genomes from 29 diverse Asian breeds, including 132 river buffaloes, 129 swamp buffaloes, and 126 crossbred buffaloes. We identified 36,548 copy number variants (CNV) spanning 133.29 Mb of the buffalo genome, resulting in 2,100 CNV regions (CNVR), with 1,993 shared CNVR being found within the studied buffalo types. Analyzing CNVR highlighted distinct genetic differentiation between river and swamp buffalo subspecies, verified by evolutionary tree and principal component analyses. Admixture analysis grouped buffaloes into river and swamp categories, with crossbred buffaloes displaying mixed ancestry. To identify candidate genes associated with milk production traits, we employed 3 approaches. First, we used Vst-based population differentiation, revealing 11 genes within CNVR that exhibited significant divergence between different buffalo breeds, including genes linked to milk production traits. Second, expression quantitative loci analysis revealed differentially expressed CNVR-derived genes (DECG) associated with milk production traits. Notably, known milk production-related genes were among these DECG, validating their relevance. Last, a GWAS identified 3 CNVR significantly linked to peak milk yield. Our study provides comprehensive genomic insights into buffalo populations and identifies candidate genes associated with milk production traits. These findings facilitate genetic breeding programs aimed at increasing milk yield and improving quality in this economically important livestock species.

Phenotypic heterogeneity in 22q11.2 deletion syndrome: CopyNumberVariants as genetic modifiers for congenital heart disease in a Brazilian cohort.

The clinical heterogeneity in 22q11.2 deletion syndrome (22q11.2DS) underlies complex genetic mechanisms including variants in other regions of the genome, known as genetic modifiers. Congenital heart disease (CHD) is one of the most relevant phenotypes in the syndrome and copy number variants (CNVs) outside the 22q11.2 region could play a role in its variable expressivity. Since those described loci account for a small proportion of the variability, the CNV analysis in new cohorts from different ancestry-based populations constitutes a valuable resource to identify a wider range of modifiers. We performed SNP-array in 117 Brazilian patients with 22q11.2DS, with and without CHD, and leveraged genome-wide CNV analysis. After quality control, we selected 50 CNVs in 38 patients for downstream analysis. CNVs' genetic content and implicated biological pathways were compared between patients with and without CHD. CNV-affected genes in patients with CHD were enriched for several functional terms related to ubiquitination, transcription factor binding sites and miRNA targets, highlighting the complexity of the phenotype's expressivity. Cardiac-related genes were identified in both groups of patients suggesting that increasing risk and protective mechanisms could be involved. These genes and enriched pathways could indicate new modifiers to the cardiac phenotype in 22q11.2DS patients.

Genomewide Association Study Identifies Copy Number Variants Associated With Warfarin Dose Response and Risk of Venous Thromboembolism in African Americans.

The anticoagulant warfarin is commonly used to control and prevent thrombotic disorders, such as venous thromboembolism (VTE), which disproportionately afflicts African Americans. Despite the importance of copy number variants (CNVs), few studies have focused on characterizing and understanding their role in drug response and disease risk among African Americans. In this study, we conduct the first genome-wide analysis of CNVs to more comprehensively account for the contribution of genetic variation in warfarin dose requirement and VTE risk among African Americans. We used hidden Markov models to detect CNVs from high-throughput single-nucleotide polymorphism arrays for 340 African American participants in the International Warfarin Pharmacogenetics Consortium. We identified 11,570 CNVs resulting in 2,038 copy number variable regions (CNVRs) and found 3 CNVRs associated with warfarin dose requirement and 3 CNVRs associated with VTE risk in African Americans. CNVRs 1q31.2del and 6q14.1del were associated with increased warfarin dose requirement (β=11.18 and 4.94, respectively; Pemp =< 0.002); CNVR 19p13.31del was associated with decreased warfarin dose requirement (β=-1.41, Pemp =0.0004); CNVRs (2p22.1del and 5q35.1-q35.2del) were found to be associated with increased risk of VTE (odds ratios (ORs)=1.88 and 14.9, respectively; Pemp ≤0.02); and CNVR 10q26.12del was associated with a decreased risk of VTE (OR=0.6; Pemp =0.05). Modeling of the 10q26.12del in HepG2 cells revealed that this deletion results in decreased fibrinogen gene expression, decreased fibrinogen and WDR11 protein levels, and decreased secretion of fibrinogen into the extracellular matrix. We found robust evidence that CNVRs could contribute to warfarin dose requirement and risk of VTE in African Americans and for 10q26.3del describe a possible pathogenic mechanism.

Copy number variants as modifiers of breast cancer risk for BRCA1/BRCA2 pathogenic variant carriers

The contribution of germline copy number variants (CNVs) to risk of developing cancer in individuals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.

Rare germline copy number variants (CNVs) and breast cancer risk

Germline copy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data. Gene burden tests detected the strongest association for deletions in BRCA1 (P = 3.7E−18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P = 0.0008), ATM (P = 0.002) and BRCA2 (P = 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci. To the best of our knowledge, this is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Genetic testing in children and adolescents with intellectual disability.

Investigation for genetic causes of intellectual disability has advanced rapidly in recent years. We review the assessment of copy number variants (CNVs) and the use of next-generation sequencing based assays to identify single nucleotide variation in intellectual disability. We discuss the diagnostic yields that can be expected with the different assays. There is high co-morbidity of intellectual disability and psychiatric disorders. We review the relationship between variants which are pathogenic for intellectual disability and the risk of child and adolescent onset psychiatric disorders. The diagnostic yields from genome wide CNV analysis and whole exome sequence analysis are high - in the region of 15 and 40%, respectively - but vary according to exact referral criteria. Many variants pathogenic for intellectual disability, notably certain recurrent CNVs, have emerged as strong risk factors for other neurodevelopmental disorders such as autism spectrum disorders, attention deficit hyperactivity disorder, and schizophrenia. It is now conceivable that etiological variants could be identified in the majority of children presenting with intellectual disability using next-generation sequencing based assays. However, challenges remain in assessment of the pathogenicity of variants, reporting of incidental findings in children and determination of prognosis, particularly in relation to psychiatric disorders.

Genome-wide copy number variant analysis reveals variants associated with 10 diverse production traits in Holstein cattle

BackgroundCopy number variation (CNV) is an important type of genetic variation contributing to phenotypic differences among mammals and may serve as an alternative molecular marker to single nucleotide polymorphism (SNP) for genome-wide association study (GWAS). Recently, GWAS analysis using CNV has been applied in livestock, although few studies have focused on Holstein cattle.ResultsWe describe 191 CNV detected using intensity data from over 700,000 SNP genotypes generated with the BovineHD Genotyping BeadChip (Illumina, San Diego, CA) in 528 Holstein cows. The CNV were used for GWAS analysis of 10 important production traits of 473 cattle related to feed intake, milk quality, and female fertility, as well as 2 composite traits of net merit and productive life. In total, we detected 57 CNV associated (P < 0.05 after false discovery rate correction) with at least one of the 10 phenotypes. Focusing on feed efficiency and intake-related phenotypes of residual feed intake and dry matter intake, we detected a single CNV associated with both traits which overlaps a predicted olfactory receptor gene OR2A2 (LOC787786). Additionally, 2 CNV within the RXFP4 (relaxin/insulin like family peptide receptor 4) and 2 additional olfactory receptor gene regions, respectively, were associated with residual feed intake. The RXFP4 gene encodes a receptor for an orexigenic peptide, insulin-like peptide 5 produced by intestinal L cells, which is expressed by enteric neurons. Olfactory receptors are critical for transmitting the effects of odorants, contributing to the sense of smell, and have been implicated in participating in appetite regulation.ConclusionsOur results identify CNV for genomic evaluation in Holstein cattle, and provide candidate genes, such as RXFP4, contributing to variation in feed efficiency and feed intake-related traits. These results indicate potential novel targets for manipulating feed intake-related traits of livestock.

The clinical impact of copy number variants in inherited bone marrow failure syndromes

Inherited bone marrow failure syndromes comprise a genetically heterogeneous group of diseases with hematopoietic failure and a wide array of physical malformations. Copy number variants were reported in some inherited bone marrow failure syndromes. It is unclear what impact copy number variants play in patients evaluated for a suspected diagnosis of inherited bone marrow failure syndromes. Clinical and genetic data of 323 patients from the Canadian Inherited Marrow Failure Registry from 2001 to 2014, who had a documented genetic work-up, were analyzed. Cases with pathogenic copy number variants (at least 1 kilobasepairs) were compared to cases with other mutations. Genotype-phenotype correlations were performed to assess the impact of copy number variants. Pathogenic nucleotide-level mutations were found in 157 of 303 tested patients (51.8%). Genome-wide copy number variant analysis by single-nucleotide polymorphism arrays or comparative genomic hybridization arrays revealed pathogenic copy number variants in 11 of 67 patients tested (16.4%). In four of these patients, identification of copy number variant was crucial for establishing the correct diagnosis as their clinical presentation was ambiguous. Eight additional patients were identified to harbor pathogenic copy number variants by other methods. Of the 19 patients with pathogenic copy number variants, four had compound-heterozygosity of a copy number variant with a nucleotide-level mutation. Pathogenic copy number variants were associated with more extensive non-hematological organ system involvement (p = 0.0006), developmental delay (p = 0.006) and short stature (p = 0.04) compared to nucleotide-level mutations. In conclusion, a significant proportion of patients with inherited bone marrow failure syndromes harbor pathogenic copy number variants which were associated with a more extensive non-hematological phenotype in this cohort. Patients with a phenotype suggestive of inherited bone marrow failure syndromes but without identification of pathogenic nucleotide-level mutations should undergo specific testing for copy number variants.

High-resolution copy number variation analysis of schizophrenia in Japan.

Recent schizophrenia (SCZ) studies have reported an increased burden of de novo copy number variants (CNVs) and identified specific high-risk CNVs, although with variable phenotype expressivity. However, the pathogenesis of SCZ has not been fully elucidated. Using array comparative genomic hybridization, we performed a high-resolution genome-wide CNV analysis on a mainly (92%) Japanese population (1699 SCZ cases and 824 controls) and identified 7066 rare CNVs, 70.0% of which were small (<100 kb). Clinically significant CNVs were significantly more frequent in cases than in controls (odds ratio=3.04, P=9.3 × 10-9, 9.0% of cases). We confirmed a significant association of X-chromosome aneuploidies with SCZ and identified 11 de novo CNVs (e.g., MBD5 deletion) in cases. In patients with clinically significant CNVs, 41.7% had a history of congenital/developmental phenotypes, and the rate of treatment resistance was significantly higher (odds ratio=2.79, P=0.0036). We found more severe clinical manifestations in patients with two clinically significant CNVs. Gene set analysis replicated previous findings (e.g., synapse, calcium signaling) and identified novel biological pathways including oxidative stress response, genomic integrity, kinase and small GTPase signaling. Furthermore, involvement of multiple SCZ candidate genes and biological pathways in the pathogenesis of SCZ was suggested in established SCZ-associated CNV loci. Our study shows the high genetic heterogeneity of SCZ and its clinical features and raises the possibility that genomic instability is involved in its pathogenesis, which may be related to the increased burden of de novo CNVs and variable expressivity of CNVs.

Low-pass whole-genome sequencing in clinical cytogenetics: a validated approach.

Chromosomal microarray analysis is the gold standard for copy-number variant (CNV) detection in prenatal and postnatal diagnosis. We aimed to determine whether next-generation sequencing (NGS) technology could be an alternative method for CNV detection in routine clinical application. Genome-wide CNV analysis (>50 kb) was performed on a multicenter group of 570 patients using a low-coverage whole-genome sequencing pipeline. These samples were referred for chromosomal analysis; CNVs (i.e., pathogenic CNVs, pCNVs) were classified according to the American College of Medical Genetics and Genomics guidelines. Overall, a total of 198 abortuses, 37 stillbirths, 149 prenatal, and 186 postnatal samples were tested. Our approach yielded results in 549 samples (96.3%). In addition to 119 subjects with aneuploidies, 103 pCNVs (74 losses and 29 gains) were identified in 82 samples, giving diagnostic yields of 53.2% (95% confidence interval: 45.8, 60.5), 14.7% (5.0, 31.1), 28.5% (21.1, 36.6), and 30.1% (23.6, 37.3) in each group, respectively. Mosaicism was observed at a level as low as 25%. Patients with chromosomal diseases or microdeletion/microduplication syndromes were diagnosed using a high-resolution genome-wide method. Our study revealed the potential of NGS to facilitate genetic diagnoses that were not evident in the prenatal and postnatal groups.Genet Med 18 9, 940-948.

RefCNV: Identification of Gene-Based Copy Number Variants Using Whole Exome Sequencing.

With rapid advances in DNA sequencing technologies, whole exome sequencing (WES) has become a popular approach for detecting somatic mutations in oncology studies. The initial intent of WES was to characterize single nucleotide variants, but it was observed that the number of sequencing reads that mapped to a genomic region correlated with the DNA copy number variants (CNVs). We propose a method RefCNV that uses a reference set to estimate the distribution of the coverage for each exon. The construction of the reference set includes an evaluation of the sources of variability in the coverage distribution. We observed that the processing steps had an impact on the coverage distribution. For each exon, we compared the observed coverage with the expected normal coverage. Thresholds for determining CNVs were selected to control the false-positive error rate. RefCNV prediction correlated significantly (r = 0.96–0.86) with CNV measured by digital polymerase chain reaction for MET (7q31), EGFR (7p12), or ERBB2 (17q12) in 13 tumor cell lines. The genome-wide CNV analysis showed a good overall correlation (Spearman’s coefficient = 0.82) between RefCNV estimation and publicly available CNV data in Cancer Cell Line Encyclopedia. RefCNV also showed better performance than three other CNV estimation methods in genome-wide CNV analysis.

Copy Number Variants Underlying Inherited Bone Marrow Failure Syndromes

Background. Inherited bone marrow failure syndromes (IBMFSs) comprise a genetically heterogeneous group of diseases with hematopoietic failure and varying degrees of physical malformations. The diagnosis of an IBMFS and categorizing the specific syndrome critically impact on clinical care; however, these are commonly challenging and rely on genetic testing. Since over 80 genes have been associated with IBMFSs and might be affected by different types of DNA aberrations, the best strategy to establish a diagnosis in a timely and cost effective manner is unknown. The aims of this study were to evaluate the role of genome-wide copy number variant (CNV) analysis in unraveling causal genetic alterations in IBMFS patients with unknown genotype and determine whether correlation exists between large CNVs and more severe phenotype.Methods. Patients from the Canadian Inherited Marrow Failure Registry (CIMFR) who were genetically investigated were included in this analysis. Genetic and clinical data were extracted and analyzed. Mann-Whitney test and Fisher's exact test were used to assess statistical significance.Results. Among 328 patients from the CIMFR who underwent molecular investigation, a causal genotype was identified in 185 cases (56.4%). 69 patients had genome-wide CNV analysis by SNP/CGH arrays, among which ten (14.5%) had positive results. In four out of ten cases who were genotyped by SNP/CGH array, genome-wide CNV analysis was critical for establishing the diagnosis. Among 308 patients who were tested for nucleotide-level mutations by either targeted gene analysis or next generation sequencing panels, casual mutations were found in 169 (54.9%). Three patients had compound heterozygosity for a CNV and nucleotide-level mutation.To determine whether large deletions are correlated with more severe phenotype we included nine additional patients with causal CNVs whose genotype was identified by MLPA (n=1), targeted FISH (n=1), DNA-qPCR analysis (n=1), Southern blotting (n=1) or metaphase cytogenetics (n=5). The causal CNVs among patients in our cohort ranged from 0.02 to 145.5 Mb in size. The most common disease associated with causal CNVs was Diamond-Blackfan anemia (four patients).Patients with CNVs tended to have significantly more non-hematological organ system involvement (p=0.03), developmental delay (mean=56% vs. 28%, p=0.03) and short stature (mean=67% vs. 40%, p=0.04) than patients with nucleotide-level mutations. The difference remained significant when we compared all patients with mutations that are predicted to result in truncation or lack of protein from the respective allele (large CNV, nonsense, and indel/ frameshift) to patients with mutations that are predicted to be hypomorphic or affect function (splicing, indel/ inframe and missense). There was no correlation between CNVs and the severity of the hematological disease.Conclusions. Most patients with IBMFSs have nucleotide-level mutations. However, a significant proportion of patients without such mutations have large CNVs that are not efficiently detected by current nucleotide-level testing methods. Therefore, genome-wide CNV analysis should be considered in IBMFS cases, where nucleotide-level sequencing does not reveal the causal mutation. Patients with IBMFSs and large CNVs had more non-hematological organ system involvement, a higher prevalence of developmental delay and short stature. This might be related to an additional impact of the CNVs on other genes close to the affected IBMFS gene or the severe damaging effect of the CNVs. DisclosuresLipton:Teva: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding.

Genome-wide copy number variant analysis for congenital ventricular septal defects in Chinese Han population.

BackgroundVentricular septal defects (VSDs) constitute the most prevalent congenital heart disease (CHD), occurs either in isolation (isolated VSD) or in combination with other cardiac defects (complex VSD). Copy number variation (CNV) has been highlighted as a possible contributing factor to the etiology of many congenital diseases. However, little is known concerning the involvement of CNVs in either isolated or complex VSDs.MethodsWe analyzed 154 unrelated Chinese individuals with VSD by chromosomal microarray analysis. The subjects were recruited from four hospitals across China. Each case underwent clinical assessment to define the type of VSD, either isolated or complex VSD. CNVs detected were categorized into syndrom related CNVs, recurrent CNVs and rare CNVs. Genes encompassed by the CNVs were analyzed using enrichment and pathway analysis.ResultsAmong 154 probands, we identified 29 rare CNVs in 26 VSD patients (16.9 %, 26/154) and 8 syndrome-related CNVs in 8 VSD patients (5.2 %, 8/154). 12 of the detected 29 rare CNVs (41.3 %) were recurrently reported in DECIPHER or ISCA database as associated with either VSD or general heart disease. Fifteen genes (5 %, 15/285) within CNVs were associated with a broad spectrum of complicated CHD. Among these15 genes, 7 genes were in “abnormal interventricular septum morphology” derived from the MGI (mouse genome informatics) database, and nine genes were associated with cardiovascular system development (GO:0072538).We also found that these VSD-related candidate genes are enriched in chromatin binding and transcription regulation, which are the biological processes underlying heart development.ConclusionsOur study demonstrates the potential clinical diagnostic utility of genomic imbalance profiling in VSD patients. Additionally, gene enrichment and pathway analysis helped us to implicate VSD related candidate genes.Electronic supplementary materialThe online version of this article (doi:10.1186/s12920-015-0163-4) contains supplementary material, which is available to authorized users.

SIRPB1 copy-number polymorphism as candidate quantitative trait locus for impulsive-disinhibited personality.

Impulsive-disinhibited personality (IDP) is a behavioral trait mainly characterized by seeking immediate gratification at the expense of more enduring or long-term gains. This trait has a major role in the development of several disinhibitory behaviors and syndromes, including psychopathy, attention-deficit and hyperactivity disorder, cluster-B personality disorders, criminality and alcoholism. Available data consistently support a strong heritable component, accounting for 30-60% of the observed variance in personality traits. A genome-wide analysis of copy-number variants was designed to identify novel genetic pathways associated with the IDP trait, using a series of 261 male participants with maximized opposite IDP scores. Quantitative trait locus analysis of candidate copy-number variants (CNVs) was conducted across the entire IDP continuum. Functional effects of associated variants were evaluated in zebrafish embryos. A common CNV mapping to the immune-related gene SIRPB1 was significantly associated with IDP scores in a dose-dependent manner (β=-0.172, P<0.017). Expression quantitative trait locus analysis of the critical region revealed higher SIRPB1 mRNA levels associated with the haplotype containing the deleted allele (P<0.0007). Epigenetic marks highlighted the presence of two potential insulators within the deleted region, confirmed by functional assays in zebrafish embryos, which suggests that SIRPB1 expression rates are affected by the presence/absence of the insulator regions. Upregulation of SIRPB1 has been described in prefrontal cortex of patients with schizophrenia, providing a link between SIRPB1 and diseases involving disinhibition and failure to control impulsivity. We propose SIRPB1 as a novel candidate gene to account for phenotypic differences observed in the IDP trait.

Copy Number Variation in Obsessive-Compulsive Disorder and Tourette Syndrome: A Cross-Disorder Study

Obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) are heritable neurodevelopmental disorders with a partially shared genetic etiology. This study represents the first genome-wide investigation of large (>500 kb), rare (<1%) copy number variants (CNVs) in OCD and the largest genome-wide CNV analysis in TS to date. The primary analyses used a cross-disorder design for 2,699 case patients (1,613 ascertained for OCD, 1,086 ascertained for TS) and 1,789 controls. Parental data facilitated a de novo analysis in 348 OCD trios. Although no global CNV burden was detected in the cross-disorder analysis or in secondary, disease-specific analyses, there was a 3.3-fold increased burden of large deletions previously associated with other neurodevelopmental disorders (p= .09). Half of these neurodevelopmental deletions were located in a single locus, 16p13.11 (5 case patient deletions: 0 control deletions, p= .08 in the current study, p= .025 compared to published controls). Three 16p13.11 deletions were confirmed de novo, providing further support for the etiological significance of this region. The overall OCD de novo rate was 1.4%, which is intermediate between published rates in controls (0.7%) and in individuals with autism or schizophrenia (2-4%). Several converging lines of evidence implicate 16p13.11 deletions in OCD, with weaker evidence for a role in TS. The trend toward increased overall neurodevelopmental CNV burden in TS and OCD suggests that deletions previously associated with other neurodevelopmental disorders may also contribute to these phenotypes.

A genomic copy number variant analysis implicates the MBD5 and HNRNPU genes in Chinese children with infantile spasms and expands the clinical spectrum of 2q23.1 deletion.

BackgroundInfantile spasms (IS) is a specific type of epileptic encephalopathy associated with severe developmental disabilities. Genetic factors are strongly implicated in IS, however, the exact genetic defects remain unknown in the majority of cases. Rare mutations in a single gene or in copy number variants (CNVs) have been implicated in IS of children in Western countries. The objective of this study was to dissect the role of copy number variations in Chinese children with infantile spasms.MethodsWe used the Agilent Human Genome CGH microarray 180 K for genome-wide detection of CNVs. Real-time qPCR was used to validate the CNVs. We performed genomic and medical annotations for individual CNVs to determine the pathogenicity of CNVs related to IS.ResultsWe report herein the first genome-wide CNV analysis in children with IS, detecting a total of 14 CNVs in a cohort of 47 Chinese children with IS. Four CNVs (4/47 = 8.5%) (1q21.1 gain; 1q44, 2q31.1, and 17p13 loss) are considered to be pathogenic. The CNV loss at 17p13.3 contains PAFAH1B1 (LIS1), a causative gene for lissencephaly. Although the CNVs at 1q21.1, 1q44, and 2q23.1 have been previously implicated in a wide spectrum of clinical features including autism spectrum disorders (ASD) and generalized seizure, our study is the first report identifying them in individuals with a primary diagnosis of IS. The CNV loss in the 1q44 region contains HNRNPU, a strong candidate gene recently suggested in IS by the whole exome sequencing of children with IS. The CNV loss at 2q23.1 includes MBD5, a methyl-DNA binding protein that is a causative gene of ASD and a candidate gene for epileptic encephalopathy. We also report a distinct clinical presentation of IS, microcephaly, intellectual disability, and absent hallux in a case with the 2q23.1 deletion.ConclusionOur findings strongly support the role of CNVs in infantile spasms and expand the clinical spectrum associate with 2q23.1 deletion. In particular, our study implicates the HNRNPU and MBD5 genes in Chinese children with IS. Our study also supports that the molecular mechanisms of infantile spasms appear conserved among different ethnic backgrounds.

Identification of rare copy number variants in high burden schizophrenia families

Over the last years, genome-wide studies consistently showed an increased burden of rare copy number variants (CNVs) in schizophrenia patients, supporting the "common disease, rare variant" hypothesis in at least a subset of patients. We hypothesize that in families with a high burden of disease, and thus probably a high genetic load influencing disease susceptibility, rare CNVs might be involved in the etiology of schizophrenia. We performed a genome-wide CNV analysis in the index patients of eight families with multiple schizophrenia affected members, and consecutively performed a detailed family analysis for the most relevant CNVs. One index patient showed a DRD5 containing duplication. A second index patient presented with an NRXN1 containing deletion and two adjacent duplications containing MYT1L and SNTG2. Detailed analysis in the subsequent families showed segregation of the identified CNVs. With this study we show the importance of screening high burden families for rare CNVs, which will not only broaden our knowledge concerning the molecular genetic mechanisms involved in schizophrenia but also allow the use of the obtained genetic data to provide better clinical care to these families in general and to non-symptomatic causal CNV carriers in particular.

Genome-wide CNV analysis replicates the association between GSTM1 deletion and bladder cancer: a support for using continuous measurement from SNP-array data

BackgroundStructural variations such as copy number variants (CNV) influence the expression of different phenotypic traits. Algorithms to identify CNVs through SNP-array platforms are available. The ability to evaluate well-characterized CNVs such as GSTM1 (1p13.3) deletion provides an important opportunity to assess their performance.Results773 cases and 759 controls from the SBC/EPICURO Study were genotyped in the GSTM1 region using TaqMan, Multiplex Ligation-dependent Probe Amplification (MLPA), and Illumina Infinium 1 M SNP-array platforms. CNV callings provided by TaqMan and MLPA were highly concordant and replicated the association between GSTM1 and bladder cancer. This was not the case when CNVs were called using Illumina 1 M data through available algorithms since no deletion was detected across the study samples. In contrast, when the Log R Ratio (LRR) was used as a continuous measure for the 5 probes contained in this locus, we were able to detect their association with bladder cancer using simple regression models or more sophisticated methods such as the ones implemented in the CNVtools package.ConclusionsThis study highlights an important limitation in the CNV calling from SNP-array data in regions of common aberrations and suggests that there may be added advantage for using LRR as a continuous measure in association tests rather than relying on calling algorithms.

Monogenic and Complex Forms of Obesity: Insights from Genetics Reveal the Leptin-Melanocortin Signaling Pathway as a Common Player

The role of genetic factors involved in the etiology of human obesity is beyond question. The identification of the hypothalamic leptin-melanocortin signaling pathway as a critical regulator in energy homeostasis and food intake has been essential for genetic research. In this review, we discuss the involvement of established and novel genes from this pathway in the pathogenesis of obesity. Their roles in monogenic and complex forms of obesity are illustrated by discussing the results of mutation analysis, candidate gene and genome-wide association studies, as well as copy number analysis. While we can conclude from these outcomes that the leptin-melanocortin pathway is of immense importance, there is still a lot of heritability that currently cannot be explained. Future studies implementing genome-wide association studies, genome-wide copy number variant analysis, and whole exome and whole-genome sequencing might aid in finding new variation in the conventional pathways and might reveal new biological pathways implicated in the pathogenesis of obesity.