Contribution Of Copy Number Variants Research Articles

Rare copy number variation in autoimmune Addison's disease.

Autoimmune Addison's disease (AAD) is a rare but life-threatening endocrine disorder caused by an autoimmune destruction of the adrenal cortex. A previous genome-wide association study (GWAS) has shown that common variants near immune-related genes, which mostly encode proteins participating in the immune response, affect the risk of developing this condition. However, little is known about the contribution of copy number variations (CNVs) to AAD susceptibility. We used the genome-wide genotyping data from Norwegian and Swedish individuals (1,182 cases and 3,810 controls) to investigate the putative role of CNVs in the AAD aetiology. Although the frequency of rare CNVs was similar between cases and controls, we observed that larger deletions (>1,000 kb) were more common among patients (OR = 4.23, 95% CI 1.85-9.66, p = 0.0002). Despite this, none of the large case-deletions were conclusively pathogenic, and the clinical presentation and an AAD-polygenic risk score were similar between cases with and without the large CNVs. Among deletions exclusive to individuals with AAD, we highlight two ultra-rare deletions in the genes LRBA and BCL2L11, which we speculate might have contributed to the polygenic risk in these carriers. In conclusion, rare CNVs do not appear to be a major cause of AAD but further studies are needed to ascertain the potential contribution of rare deletions to the polygenic load of AAD susceptibility.

11p13 microduplication: a differential diagnosis of Silver–Russell syndrome?

BackgroundSilver–Russel syndrome (SRS) is a congenital disorder which is mainly characterized by intrauterine and postnatal growth retardation, relative macrocephaly, and characteristic (facial) dysmorphisms. The majority of patients shows a hypomethylation of the imprinting center region 1 (IC1) in 11p15 and maternal uniparental disomy of chromosome 7 (upd(7)mat), but in addition a broad spectrum of copy number variations (CNVs) and monogenetic variants (SNVs) has been reported in this cohort. These heterogeneous findings reflect the clinical overlap of SRS with other congenital disorders, but some of the CNVs are recurrent and have therefore been suggested as SRS-associated loci. However, this molecular heterogeneity makes the decision on the diagnostic workup of patients with SRS features challenging. Case presentationA girl with clinical features of SRS but negatively tested for the IC1 hypomethylation and upd(7)mat was analyzed by whole genome sequencing in order to address both CNVs and SNVs in the same run. We identified a 11p13 microduplication affecting a region overlapping with a variant reported in a previously published patient with clinical features of Silver–Russel syndrome.ConclusionsThe identification of a 11p13 microduplication in a patient with SRS features confirms the considerable contribution of CNVs to SRS-related phenotypes, and it strengthens the evidence for a 11p13 microduplication syndrome as a differential diagnosis SRS. Furthermore, we could confirm that WGS is a valuable diagnostic tool in patients with SRS and related disorders, as it allows CNVs and SNV detection in the same run, thereby avoiding a time-consuming diagnostic testing process.

Copy Number Variations in Pancreatic Cancer: From Biological Significance to Clinical Utility.

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer, characterized by high tumor heterogeneity and a poor prognosis. Inter- and intra-tumoral heterogeneity in PDAC is a major obstacle to effective PDAC treatment; therefore, it is highly desirable to explore the tumor heterogeneity and underlying mechanisms for the improvement of PDAC prognosis. Gene copy number variations (CNVs) are increasingly recognized as a common and heritable source of inter-individual variation in genomic sequence. In this review, we outline the origin, main characteristics, and pathological aspects of CNVs. We then describe the occurrence of CNVs in PDAC, including those that have been clearly shown to have a pathogenic role, and further highlight some key examples of their involvement in tumor development and progression. The ability to efficiently identify and analyze CNVs in tumor samples is important to support translational research and foster precision oncology, as copy number variants can be utilized to guide clinical decisions. We provide insights into understanding the CNV landscapes and the role of both somatic and germline CNVs in PDAC, which could lead to significant advances in diagnosis, prognosis, and treatment. Although there has been significant progress in this field, understanding the full contribution of CNVs to the genetic basis of PDAC will require further research, with more accurate CNV assays such as single-cell techniques and larger cohorts than have been performed to date.

Contribution of copy number variants to the genetic etiology of dilated cardiomyopathy

Abstract Background/Introduction Dilated cardiomyopathy (DCM) is one of the most common cardiomyopathies, with a prevalence of 1 in 250. Single nucleotide variants (missense, nonsense, or frameshift) in definitive DCM genes are the most frequently identified in positive genetic studies. Despite major advances in genetic diagnostic technologies in recent decades, and more than 100 genes potentially associated with DCM identified to date, the diagnostic yield is still lower than 40%. Copy number variants (CNVs) have been identified as cause of the disease in several studies, especially in genes intolerant to haploinsufficiency. However, the contribution of CNVs to the etiology of DCM has not been evaluated in large cohorts of DCM patients and remains unknown. Purpose To determine the percentage of cases in which CNVs have been identified as the cause of disease in a large cohort of DCM patients evaluated genetically. Methods Retrospective study in which the presence of CNVs was evaluated in a cohort of patients diagnosed with DCM and studied by next-generation-sequencing (NGS). CNVs were detected using a read depth approach and confirmed by an orthogonal molecular technique (Sanger sequencing, MLPA, or dPCR). Results 6,512 DCM patients referred for genetic testing were sequenced in our center by NGS, and the median age at the time of genetic study was 51.1 years (range 0-93). A pathogenic (P) or likely-pathogenic (LP) disease-causing variant was identified in 1,495 of the patients (diagnostic yield of 22.9%). In 67 (1.02%) of the cases, a CNV classified as P/LP was identified. DMD was the gene with the highest number of CNVs identified (n=40), followed by TTN (n=7) and LMNA (n=5). Of the 67 cases, 45 (67%) corresponded to deletions, with a lesser extent to duplications (n=9; 13%), complex alterations (n=7; 11%), and deletion/insertion (n=6; 9%). Only two of the patients harboring disease-causing CNVs had other variants potentially associated with DCM: a likely-pathogenic variant in MYH7 and a homozygous pathogenic variant in the ALMS1 gene. Conclusion In our cohort of DCM patients, 1.02% harbored CNVs considered P/LP, being DMD the most frequently identified gene. These results show that systematic CNVs analysis in NGS studies improves the yield of genetic testing in DCM and highlights the importance of a complete genetic study that includes structural variant detection in the diagnosis of the disease.

Small but Clinically Relevant Contribution of Copy Number Variations (CNVs) to Idiopathic Nephrotic Syndrome

Small but Clinically Relevant Contribution of Copy Number Variations (CNVs) to Idiopathic Nephrotic Syndrome

Genetic Investigations in Turkish Idiopathic Pancreatitis Patients Show Unique Characteristics.

Pancreatitis is one of the leading causes of digestive system-related hospital admissions, and it has a genetic background in a considerable portion of the patients. In this study, we aimed to investigate the genetic risk factors of idiopathic pancreatitis in Turkish patients and the contribution of copy number variations to the pathogenesis. Idiopathic pancreatitis is defined as failure to detect risk factors despite comprehensive clinical assessments. Next-generation sequencing and multiple ligand-dependent probe amplification of PRSS1, SPINK1, CTRC, and CFTR were performed. For further genotype-phenotype correlations, patients were also questioned for the age of onset, family history, and pancreatic divisum. A total of 68 idiopathic pancreatitis cases were enrolled. Variants with potential clinical significance of PRSS1 were identified in 13.4%, SPINK1 in 6.3%, CTRC in 4.7%, and CFTR in 26.5% of the patients. No copy number variants were seen in any of these genes. At least 7.4% of the participants had complex genetic etiology involving 2 genes. At least 42.6% of the participants had a potential genetic risk factor. Five novel genetic variants were identified, and distinctive genetic risk factors of Turkish population were shown. The results showed that genetic etiology was frequent in pancreatitis and it was even more prominent in patients with early-onset disease. Considering that genetic risk factors may be informative for decisionmaking in the treatment options in addition to providing extensive prognostic value and familial genetic consultation; clinicians need to be more eager to offer genetic tests to pancreatitis patients.

Chromosomal microarray analysis supplements exome sequencing to diagnose children with suspected inborn errors of immunity.

Though copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. We sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with IEI. We performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. Of the 332 probands, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic molecular findings from both ES and CMA, including two compound heterozygotes and one participant with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5% beyond ES alone. Pairing ES and CMA can provide a comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

Chromosomal microarray analysis reveals copy number variants contribute to disease in children with suspected inborn errors of immunity

BackgroundThough copy number variants (CNVs) have been suggested to play a significant role in inborn errors of immunity (IEI), the precise nature of this role remains largely unexplored. Thus, we sought to determine the diagnostic contribution of CNVs using genome-wide chromosomal microarray analysis (CMA) in children with suspected or known IEI. MethodsWe performed exome sequencing (ES) and CMA for 332 unrelated pediatric probands referred for evaluation of IEI. The analysis included primary, secondary, and incidental findings. All cases were reanalyzed following the 2022 update to the International Union of Immunological Societies (IUIS) gene list. We reviewed variants that were not in the Human Gene Mutation Database (HGMD) at the time of analysis but have since been reported in the literature. Additionally, we reviewed CNVs called using GATK-SV in 11 participants who received follow-up genome sequencing, with a focus on CNVs in new IUIS genes that could have been missed by prior CMA. ResultsOur cohort included 332 probands under 18 years old (M = 9.9 years, SD = 4.3 years) at the time of enrollment. Participants were 56.6% male. Of the 332 participants, 134 (40.4%) received molecular diagnoses. Of these, 116/134 (86.6%) were diagnosed by ES alone. An additional 15/134 (11.2%) were diagnosed by CMA alone, including two likely de novo changes. Three (2.2%) participants had diagnostic findings from both ES and CMA, including two compound heterozygotes and one patient with two distinct diagnoses. Half of the participants with CMA contribution to diagnosis had CNVs in at least one non-immune gene, highlighting the clinical complexity of these cases. Reanalysis considering the 2022 IUIS gene list did not result in any new CMA diagnoses or change any existing diagnoses. Overall, CMA contributed to 18/134 diagnoses (13.4%), increasing the overall diagnostic yield by 15.5%. DiscussionPairing ES and CMA can provide a more comprehensive evaluation to clarify the complex factors that contribute to both immune and non-immune phenotypes. Such a combined approach to genetic testing helps untangle complex phenotypes, not only by clarifying the differential diagnosis, but in some cases by identifying multiple diagnoses contributing to the overall clinical presentation.

The contribution of copy number variants to psychiatric symptoms and cognitive ability.

Copy number variants (CNVs) are deletions and duplications of DNA sequence. The most frequently studied CNVs, which are described in this review, are recurrent CNVs that occur in the same locations on the genome. These CNVs have been strongly implicated in neurodevelopmental disorders, namely autism spectrum disorder (ASD), intellectual disability (ID), and developmental delay (DD), but also in schizophrenia. More recent work has also shown that CNVs increase risk for other psychiatric disorders, namely, depression, bipolar disorder, and post-traumatic stress disorder. Many of the same CNVs are implicated across all of these disorders, and these neuropsychiatric CNVs are also associated with cognitive ability in the general population, as well as with structural and functional brain alterations. Neuropsychiatric CNVs also show incomplete penetrance, such that carriers do not always develop any psychiatric disorder, and may show only mild symptoms, if any. Variable expressivity, whereby the same CNVs are associated with many different phenotypes of varied severity, also points to highly complex mechanisms underlying disease risk in CNV carriers. Comprehensive and longitudinal phenotyping studies of individual CNVs have provided initial insights into these mechanisms. However, more work is needed to estimate and predict the effect of non-recurrent, ultra-rare CNVs, which also contribute to psychiatric and cognitive outcomes. Moreover, delineating the broader phenotypic landscape of neuropsychiatric CNVs in both clinical and general population cohorts may also offer important mechanistic insights.

Genome-wide analysis of copy-number variation in humans with cleft lip and/or cleft palate identifies COBLL1, RIC1, and ARHGEF38 as clefting genes

Cleft lip with or without cleft palate (CL/P) is a common birth defect with a complex, heterogeneous etiology. It is well established that common and rare sequence variants contribute to the formation of CL/P, but the contribution of copy-number variants (CNVs) to cleft formation remains relatively understudied. To fill this knowledge gap, we conducted a large-scale comparative analysis of genome-wide CNV profiles of 869 individuals from the Philippines and 233 individuals of European ancestry with CL/P with three primary goals: first, to evaluate whether differences in CNV number, amount of genomic content, or amount of coding genomic content existed within clefting subtypes; second, to assess whether CNVs in our cohort overlapped with known Mendelian clefting loci; and third, to identify unestablished Mendelian clefting genes. Significant differences in CNVs across cleft types or in individuals with non-syndromic versus syndromic clefts were not observed; however, several CNVs in our cohort overlapped with known syndromic and non-syndromic Mendelian clefting loci. Moreover, employing a filtering strategy relying on population genetics data that rare variants are on the whole more deleterious than common variants, we identify several CNV-associated gene losses likely driving non-syndromic clefting phenotypes. By prioritizing genes deleted at a rare frequency across multiple individuals with clefts yet enriched in our cohort of individuals with clefts compared to control subjects, we identify COBLL1, RIC1, and ARHGEF38 as clefting genes. CRISPR-Cas9 mutagenesis of these genes in Xenopus laevis and Danio rerio yielded craniofacial dysmorphologies, including clefts analogous to those seen in human clefting disorders.

Genome-wide identification of disease-causing copy number variations in 450 individuals with anorectal malformations

Anorectal malformations (ARM) represent a spectrum of rare malformations originating from a perturbated development of the embryonic hindgut. Approximately 60% occur as a part of a defined genetic syndrome or within the spectrum of additional congenital anomalies. Rare copy number variations (CNVs) have been associated with both syndromic and non-syndromic forms. The present study represents the largest study to date to explore the contribution of CNVs to the expression of ARMs. SNP-array-based molecular karyotyping was applied in 450 individuals with ARM and 4392 healthy controls. CNVs were identified from raw intensity data using PennCNV. Overlapping CNVs between cases and controls were discarded. Remaining CNVs were filtered using a stringent filter algorithm of nine filter steps. Prioritized CNVs were confirmed using qPCR. Filtering prioritized and qPCR confirmed four microscopic chromosomal anomalies and nine submicroscopic CNVs comprising seven microdeletions (del2p13.2, del4p16.2, del7q31.33, del9p24.1, del16q12.1, del18q32, del22q11.21) and two microduplications (dup2p13.2, dup17q12) in 14 individuals (12 singletons and one affected sib-pair). Within these CNVs, based on their embryonic expression data and function, we suggest FOXK2, LPP, and SALL3 as putative candidate genes. Overall, our CNV analysis identified putative microscopic and submicroscopic chromosomal rearrangements in 3% of cases. Functional characterization and re-sequencing of suggested candidate genes is warranted.

Investigating the contributions of circadian pathway and insomnia risk genes to autism and sleep disturbances

Sleep disturbance is prevalent in youth with Autism Spectrum Disorder (ASD). Researchers have posited that circadian dysfunction may contribute to sleep problems or exacerbate ASD symptomatology. However, there is limited genetic evidence of this. It is also unclear how insomnia risk genes identified through GWAS in general populations are related to ASD and common sleep problems like insomnia traits in ASD. We investigated the contribution of copy number variants (CNVs) encompassing circadian pathway genes and insomnia risk genes to ASD risk as well as sleep disturbances in children with ASD. We studied 5860 ASD probands and 2092 unaffected siblings from the Simons Simplex Collection (SSC) and MSSNG database, as well as 7509 individuals from two unselected populations (IMAGEN and Generation Scotland). Sleep duration and insomnia symptoms were parent reported for SSC probands. We identified 335 and 616 rare CNVs encompassing circadian and insomnia risk genes respectively. Deletions and duplications with circadian genes were overrepresented in ASD probands compared to siblings and unselected controls. For insomnia-risk genes, deletions (not duplications) were associated with ASD in both cohorts. Results remained significant after adjusting for cognitive ability. CNVs containing circadian pathway and insomnia risk genes showed a stronger association with ASD, compared to CNVs containing other genes. Circadian genes did not influence sleep duration or insomnia traits in ASD. Insomnia risk genes intolerant to haploinsufficiency increased risk for insomnia when duplicated. CNVs encompassing circadian and insomnia risk genes increase ASD liability with little to no observable impacts on sleep disturbances.

Dissection of mendelian predisposition and complex genetic architecture of craniovertebral junction malformation.

The craniovertebral junction (CVJ) is an anatomically complex region of the axial skeleton that provides protection of the brainstem and the upper cervical spinal cord. Structural malformation of the CVJ gives rise to life-threatening neurological deficits, such as quadriplegia and dyspnea. Unfortunately, genetic studies on human subjects with CVJ malformation are limited and the pathogenesis remains largely elusive. In this study, we recruited 93 individuals with CVJ malformation and performed exome sequencing. Manual interpretation of the data identified three pathogenic variants in genes associated with Mendelian diseases, including CSNK2A1, MSX2, and DDX3X. In addition, the contribution of copy number variations (CNVs) to CVJ malformation was investigated and three pathogenic CNVs were identified in three affected individuals. To further dissect the complex mutational architecture of CVJ malformation, we performed a gene-based rare variant association analysis utilizing 4371 in-house exomes as control. Rare variants in LGI4 (carrier rate = 3.26%, p = 3.3 × 10-5) and BEST1 (carrier rate = 5.43%, p = 5.77 × 10-6) were identified to be associated with CVJ malformation. Furthermore, gene set analyses revealed that extracellular matrix- and RHO GTPase-associated biological pathways were found to be involved in the etiology of CVJ malformation. Overall, we comprehensively dissected the genetic underpinnings of CVJ malformation and identified several novel disease-associated genes and biological pathways.

Contribution of copy number variations to the risk of severe eating disorders

AimEating disorders (EDs) are complex, multifactorial psychiatric conditions. Previous studies identified pathogenic copy number variations associated with NDDs (NDD‐CNVs) in ED patients. However, no statistical evidence for an association between NDD‐CNVs and EDs has been demonstrated. Therefore, we examined whether NDD‐CNVs confer risk for EDs.MethodsUsing array comparative genomic hybridization (aCGH), we conducted a high‐resolution CNV analysis of 71 severe female ED patients and 1045 female controls. According to the American College of Medical Genetics guidelines, we identified NDD‐CNVs or pathogenic/likely pathogenic CNVs in NDD‐linked loci. Gene set analysis was performed to examine the involvement of synaptic dysfunction in EDs. Clinical data were retrospectively examined for ED patients with NDD‐CNVs.ResultsOf the samples analyzed with aCGH, 70 severe ED patients (98.6%) and 1036 controls (99.1%) passed our quality control filtering. We obtained 189 and 2539 rare CNVs from patients and controls, respectively. NDD‐CNVs were identified in 10.0% (7/70) of patients and 2.3% (24/1036) of controls. Statistical analysis revealed a significant association between NDD‐CNVs and EDs (odds ratio = 4.69, P = 0.0023). NDD‐CNVs in ED patients included 45,X and deletions at KATNAL2, DIP2A, PTPRT, RBFOX1, CNTN4, MACROD2, and FAM92B. Four of these genes were related to synaptic function. In gene set analysis, we observed a nominally significant enrichment of rare exonic CNVs in synaptic signaling in ED patients (odds ratio = 2.55, P = 0.0254).ConclusionOur study provides the first preliminary evidence that NDD‐CNVs may confer risk for severe EDs. The pathophysiology may involve synaptic dysfunction.

Evaluation of copy number variants for genetic hearing loss: a review of current approaches and recent findings.

Structural variation includes a change in copy number, orientation, or location of a part of the genome. Copy number variants (CNVs) are a common cause of genetic hearing loss, comprising nearly 20% of diagnosed cases. While large deletions involving the gene STRC are the most common pathogenic CNVs, a significant proportion of known hearing loss genes also contain pathogenic CNVs. In this review, we provide an overview of currently used methods for detection of CNVs in genes known to cause hearing loss including molecular techniques such as multiplex ligation probe amplification (MLPA) and digital droplet polymerase chain reaction (ddPCR), array-CGH and single-nucleotide polymorphism (SNP) arrays, as well as techniques for detection of CNVs using next-generation sequencing data analysis including targeted gene panel, exome, and genome sequencing data. In addition, in this review, we compile published data on pathogenic hearing loss CNVs to provide an up-to-date overview. We show that CNVs have been identified in 29 different non-syndromic hearing loss genes. An understanding of the contribution of CNVs to genetic hearing loss is critical to the current diagnosis of hearing loss and is crucial for future gene therapies. Thus, evaluation for CNVs is required in any modern pipeline for genetic diagnosis of hearing loss.

The Contribution of Copy Number Variants and Single Nucleotide Polymorphisms to the Additive Genetic Variance of Carcass Traits in Cattle.

The relative contributions of both copy number variants (CNVs) and single nucleotide polymorphisms (SNPs) to the additive genetic variance of carcass traits in cattle is not well understood. A detailed understanding of the relative importance of CNVs in cattle may have implications for study design of both genomic predictions and genome-wide association studies. The first objective of the present study was to quantify the relative contributions of CNV data and SNP genotype data to the additive genetic variance of carcass weight, fat, and conformation for 945 Charolais, 923 Holstein-Friesian, and 974 Limousin sires. The second objective was to jointly consider SNP and CNV data in a least absolute selection and shrinkage operator (LASSO) regression model to identify genomic regions associated with carcass weight, fat, and conformation within each of the three breeds separately. A genomic relationship matrix (GRM) based on just CNV data did not capture any variance in the three carcass traits when jointly evaluated with a SNP-derived GRM. In the LASSO regression analysis, a total of 987 SNPs and 18 CNVs were associated with at least one of the three carcass traits in at least one of the three breeds. The quantitative trait loci (QTLs) corresponding to the associated SNPs and CNVs overlapped with several candidate genes including previously reported candidate genes such as MSTN and RSAD2, and several potential novel candidate genes such as ACTN2 and THOC1. The results of the LASSO regression analysis demonstrated that CNVs can be used to detect associations with carcass traits which were not detected using the set of SNPs available in the present study. Therefore, the CNVs and SNPs available in the present study were not redundant forms of genomic data.

CCL3L3-null status is associated with susceptibility to systemic lupus erythematosus

The correlation between copy number variation (CNV) and the susceptibility to systemic lupus erythematosus (SLE) has been reported for various immunity-related genes. However, the contribution of CNVs to SLE susceptibility awaits more investigation. To evaluate the copy numbers in immunity-related genes such as TNFAIP3, TNIP1, IL12B, TBX21 (T-bet), TLR7, C4A, C4B, CCL3L1, and CCL3L3, the modified real competitive polymerase chain reaction (mrcPCR) assay was employed, and the association between the copy numbers and SLE susceptibility was analyzed in 334 SLE patients and 338 controls. CCL3L3-null status was significantly associated with SLE susceptibility (OR > 18, P < 0.0001), which remained significant by Bonferroni’s correction (corrected P = 0.0007). However, the significant association between C4B low-copy status and SLE susceptibility (OR = 1.6051, P = 0.0331) became non-significant by Bonferroni’s correction (corrected P = 0.3938). Except for these results, no other significant association between SLE susceptibility and copy number status in other genes was observed. The CCL3L3-null status may be a significant factor for SLE susceptibility.

Konjenital Bilateral Vas Deferens Yokluğu Olan Türk Hastalarda Genomik Kopya Sayısı Varyasyonları Analizi

Aim: Congenital Bilateral Absence of the Vas Deferens (CBAVD) is a developmental abnormality that causes infertility in males. According to the literature, up to 88% of CBAVD cases have at least one pathogenic Cystic Fibrosis Transmembrane Conductance Regulator gene (CFTR) mutation. However, based on our previous data, this rate was 15.90% in Turkish patients with CBAVD. We aimed to identify genomic copy number variations (CNV) and candidate genomic regions which could related to the CBAVD in Turkish population.Methods: CNV analysis was performed in 19 Turkish CBAVD patients normal karyotypes and a wild type CFTR genotype. We suggested that the DAD1 gene may be a candidate gene related to CBAVD by reviewing online databases and analyzing CNV findings. Sanger sequencing of the DAD1 gene exons was performed in 22 patients.Results: We identified 11 CNVs that most likely related with the disease in nine of 19 (47.3%) patients. As the most common CNV, 14q11.2 deletions were detected in there (15.79%) of the patients. There was only DAD1 gene in the sharing genomic region of two of the 14q11.2 deletions. No sequence variation was detected in the DAD1 gene of the patients.Conclusion: The 14q11.2 chromosomal region and the DAD1 gene may be associated with CBAVD. Further studies are needed to indentify the contribution of CNVs and DAD1 gene to CBAVD etiology.

Genome-wide CNV investigation suggests a role for cadherin, Wnt, and p53 pathways in primary open-angle glaucoma

BackgroundTo investigate whether copy number variations (CNVs) are implicated in molecular mechanisms underlying primary open-angle glaucoma (POAG), we used genotype data of POAG individuals and healthy controls from two case-control studies, AGS (n = 278) and GLGS-UGLI (n = 1292). PennCNV, QuantiSNP, and cnvPartition programs were used to detect CNV. Stringent quality controls at both sample and marker levels were applied. The identified CNVs were intersected in CNV region (CNVR). After, we performed burden analysis, CNV-genome-wide association analysis, gene set overrepresentation and pathway analysis. In addition, in human eye tissues we assessed the expression of the genes lying within significant CNVRs.ResultsWe reported a statistically significant greater burden of CNVs in POAG cases compared to controls (p-value = 0,007). In common between the two cohorts, CNV-association analysis identified statistically significant CNVRs associated with POAG that span 11 genes (APC, BRCA2, COL3A1, HLA-DRB1, HLA-DRB5, HLA-DRB6, MFSD8, NIPBL, SCN1A, SDHB, and ZDHHC11). Functional annotation and pathway analysis suggested the involvement of cadherin, Wnt signalling, and p53 pathways.ConclusionsOur data suggest that CNVs may have a role in the susceptibility of POAG and they can reveal more information on the mechanism behind this disease. Additional genetic and functional studies are warranted to ascertain the contribution of CNVs in POAG.

Analysis of copy number variations of WNT4 gene in a Chinese population with M\xfcllerian anomalies

BackgroundTo investigate the genetic contribution of copy number variations (CNVs) in Wingless-type MMTV integration site family, member 4 (WNT4), in a Chinese population with Müllerian anomalies (MA), copy number analysis of WNT4 by Multiplex ligation‐dependent probe amplification (MLPA) was performed on 248 female patients. Some studies have shown that heterozygous missense mutation of WNT4 can lead to MA. However, few studies on the relationship between WNT4 CNVs and MA have been performed.ResultsAmong the 248 Chinese women affected by MA in this study, heterozygous deletion of WNT4 was detected in a single patient.ConclusionsMLPA identified one heterozygous deletion in WNT4 in a single female patient among 248 Chinese women affected by MA. This study firstly reports CNVs of WNT4 in a large sample of MA patients from the Chinese population, which suggests that CNVs of WNT4 cannot be excluded in the occurrence of MA. This provides a genetic basis for precise treatment in the future.