An Excess of Deleterious Variants in VEGF-A Pathway Genes in Down-Syndrome-Associated Atrioventricular Septal Defects

About half of people with trisomy 21 have a congenital heart defect (CHD), whereas the remainder have a structurally normal heart, demonstrating that trisomy 21 is a significant risk factor but is not causal for abnormal heart development. Atrioventricular septal defects (AVSD) are the most commonly occurring heart defects in Down syndrome (DS), and ∼65% of all AVSD is associated with DS. We used a candidate-gene approach among individuals with DS and complete AVSD (cases = 141) and DS with no CHD (controls = 141) to determine whether rare genetic variants in genes involved in atrioventricular valvuloseptal morphogenesis contribute to AVSD in this sensitized population. We found a significant excess (p < 0.0001) of variants predicted to be deleterious in cases compared to controls. At the most stringent level of filtering, we found potentially damaging variants in nearly 20% of cases but fewer than 3% of controls. The variants with the highest probability of being damaging in cases only were found in six genes: COL6A1, COL6A2, CRELD1, FBLN2, FRZB, and GATA5. Several of the case-specific variants were recurrent in unrelated individuals, occurring in 10% of cases studied. No variants with an equal probability of being damaging were found in controls, demonstrating a highly specific association with AVSD. Of note, all of these genes are in the VEGF-A pathway, even though the candidate genes analyzed in this study represented numerous biochemical and developmental pathways, suggesting that rare variants in the VEGF-A pathway might contribute to the genetic underpinnings of AVSD in humans.     

ECE1 polymorphisms may contribute to the susceptibility of sporadic congenital heart disease in a Chinese population

Endothelin-converting enzyme-1 (ECE1) plays a key role in the development of a subset of neural crest lineages such as cardiogenesis. Genetic variants of ECE1 C338A (rs213045) and T839G (rs213046) have been shown to alter ECE1 expression. This observation led us to hypothesize that two polymorphisms might influence the susceptibility of sporadic congenital heart disease (CHD). We conducted a case-control study comprised of 945 CHD cases and 972 non-CHD controls in a Chinese population. We tested our hypothesis by genotyping ECE1 C338A and T839G and assessed their association with the risk of CHD. Compared with the 338 CC and the 839 TT genotypes, the ECE1 338 AA/AC and 839 TG/GG genotypes significantly increased the risk of CHD (adjusted odds ratio [OR]=1.38, 95% confidence interval [CI]=1.14-1.68; and adjusted OR=1.30, 95% CI=1.07-1.58, respectively). A combined analysis was performed that showed that the presence of 2-4 risk alleles (the ECE1 338A and 839G allele) increased the risk of CHD by 2.07-fold compared with 0-1 risk alleles. Furthermore, we found that the association between 2-4 risk alleles and CHD risk was stronger in females (adjusted OR=1.77, 95% CI=1.31-2.40) than males (adjusted OR=1.33, 95% CI=1.03-1.71), and in the phenotypes of Tetralogy of Fallot (adjusted OR=1.84, 95% CI=1.10-3.06) and perimembranous ventricular septal defect (pmVSD) (adjusted OR=1.74, 95% CI=1.35-2.24). Our results suggest that ECE1 polymorphisms may contribute to the susceptibility of sporadic CHD in a Chinese population.     

Common genetic variants and modification of penetrance of BRCA2-associated breast cancer

The considerable uncertainty regarding cancer risks associated with inherited mutations of BRCA2 is due to unknown factors. To investigate whether common genetic variants modify penetrance for BRCA2 mutation carriers, we undertook a two-staged genome-wide association study in BRCA2 mutation carriers. In stage 1 using the Affymetrix 6.0 platform, 592,163 filtered SNPs genotyped were available on 899 young (<40 years) affected and 804 unaffected carriers of European ancestry. Associations were evaluated using a survival-based score test adjusted for familial correlations and stratified by country of the study and BRCA2*6174delT mutation status. The genomic inflation factor (λ) was 1.011. The stage 1 association analysis revealed multiple variants associated with breast cancer risk: 3 SNPs had p-values<10(-5) and 39 SNPs had p-values<10(-4). These variants included several previously associated with sporadic breast cancer risk and two novel loci on chromosome 20 (rs311499) and chromosome 10 (rs16917302). The chromosome 10 locus was in ZNF365, which contains another variant that has recently been associated with breast cancer in an independent study of unselected cases. In stage 2, the top 85 loci from stage 1 were genotyped in 1,264 cases and 1,222 controls. Hazard ratios (HR) and 95% confidence intervals (CI) for stage 1 and 2 were combined and estimated using a retrospective likelihood approach, stratified by country of residence and the most common mutation, BRCA2*6174delT. The combined per allele HR of the minor allele for the novel loci rs16917302 was 0.75 (95% CI 0.66-0.86, ) and for rs311499 was 0.72 (95% CI 0.61-0.85, ). FGFR2 rs2981575 had the strongest association with breast cancer risk (per allele HR = 1.28, 95% CI 1.18-1.39, ). These results indicate that SNPs that modify BRCA2 penetrance identified by an agnostic approach thus far are limited to variants that also modify risk of sporadic BRCA2 wild-type breast cancer.     

Genetic Variants on Chromosome 1p13.3 Are Associated with Non-ST Elevation Myocardial Infarction and the Expression of DRAM2 in the Finnish Population

Myocardial infarction (MI) is divided into either ST elevation MI (STEMI) or non-ST elevation MI (NSTEMI), differing in a number of clinical characteristics. We sought to identify genetic variants conferring risk to NSTEMI or STEMI by conducting a genome-wide association study (GWAS) of MI stratified into NSTEMI and STEMI in a consecutive sample of 1,579 acute MI cases with 1,576 controls. Subsequently, we followed the results in an independent population-based sample of 562 cases and 566 controls, a partially independent prospective cohort (N = 16,627 with 163 incident NSTEMI cases), and examined the effect of disease-associated variants on gene expression in 513 healthy participants. Genetic variants on chromosome 1p13.3 near the damage-regulated autophagy modulator 2 gene DRAM2 associated with NSTEMI (rs656843; odds ratio 1.57, P = 3.11 × 10⁻¹⁰) in the case-control analysis with a consistent but not statistically significant effect in the prospective cohort (rs656843; hazard ratio 1.13, P = 0.43). These variants were not associated with STEMI (rs656843; odds ratio, 1.11, P = 0.20; hazard ratio 0.97, P = 0.87), appearing to have a pronounced effect on NSTEMI risk. A majority of the variants at 1p13.3 associated with NSTEMI were also associated with the expression level of DRAM2 in blood leukocytes of healthy controls (top-ranked variant rs325927, P = 1.50 × 10⁻¹²). The results suggest that genetic factors may in part influence whether coronary artery disease results in NSTEMI rather than STEMI.     

Pooled Sequencing of 531 Genes in Inflammatory Bowel Disease Identifies an Associated Rare Variant in BTNL2 and Implicates Other Immune Related Genes

The contribution of rare coding sequence variants to genetic susceptibility in complex disorders is an important but unresolved question. Most studies thus far have investigated a limited number of genes from regions which contain common disease associated variants. Here we investigate this in inflammatory bowel disease by sequencing the exons and proximal promoters of 531 genes selected from both genome-wide association studies and pathway analysis in pooled DNA panels from 474 cases of Crohn’s disease and 480 controls. 80 variants with evidence of association in the sequencing experiment or with potential functional significance were selected for follow up genotyping in 6,507 IBD cases and 3,064 population controls. The top 5 disease associated variants were genotyped in an extension panel of 3,662 IBD cases and 3,639 controls, and tested for association in a combined analysis of 10,147 IBD cases and 7,008 controls. A rare coding variant p.G454C in the BTNL2 gene within the major histocompatibility complex was significantly associated with increased risk for IBD (p = 9.65x10⁻¹⁰, OR = 2.3[95% CI = 1.75–3.04]), but was independent of the known common associated CD and UC variants at this locus. Rare (<1%) and low frequency (1–5%) variants in 3 additional genes showed suggestive association (p<0.005) with either an increased risk (ARIH2 c.338-6C>T) or decreased risk (IL12B p.V298F, and NICN p.H191R) of IBD. These results provide additional insights into the involvement of the inhibition of T cell activation in the development of both sub-phenotypes of inflammatory bowel disease. We suggest that although rare coding variants may make a modest overall contribution to complex disease susceptibility, they can inform our understanding of the molecular pathways that contribute to pathogenesis.     

Whole Exome Sequencing in Patients with the Cuticular Drusen Subtype of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is the leading cause of irreversible blindness in elderly people worldwide. Cuticular drusen (CD) is a clinical subtype of AMD, which typically displays an earlier age at onset, and has a strong genetic component. Genetic studies support a role for rare sequence variants in CD susceptibility, and rare sequence variants in the CFH gene have been identified in 8.8% of CD cases. To further explore the role of rare variants in CD, we performed whole exome sequencing (WES) in 14 affected members of six families and 12 sporadic cases with CD. We detected rare sequence variants in CFH and FBLN5, which previously were shown to harbor rare variants in patients with CD. In addition, we detected heterozygous rare sequence variants in several genes encoding components of the extracellular matrix (ECM), including FBLN1, FBLN3/EFEMP1, FBLN5, FBLN6/HMCN1, FBN2, and COL15A1. Two rare pathogenic variants were identified in the COL15A1 gene: one in a sporadic case and another was found to segregate in a family with six affected individuals with CD. In addition, two rare pathogenic variants were identified in the FGL1 gene in three unrelated CD cases. These findings suggest that alterations in the ECM and in the coagulation pathway may play a role in the pathogenesis of CD. The identified candidate genes require further analyses in larger cohorts to confirm their role in the CD subtype of AMD. No evidence was found of rare sequence variants in a single gene that segregate with CD in the six families, suggesting that the disease is genetically heterogeneous.     

COL9A1 Gene Polymorphism Is Associated with Kashin-Beck Disease in a Northwest Chinese Han Population

Objective

We sought to determine whether genomic polymorphism in collagen IX genes (COL9A) was associated with Kashin-Beck disease (KBD).

Methods

Twenty seven single nucleotide polymorphisms (SNPs) in COL9AI, COL9A2 and COL9A3 were genotyped in 274 KBD cases and 248 healthy controls using the Sequenom MassARRAY system. Associations between the COL9A polymorphism and KBD risk were detected using an unconditional logistic regression model. Linkage disequilibrium (LD) and haplotypes analysis were performed with the Haploview software.

Results

After Bonferroni correction, the frequency distribution of genotypes in rs6910140 in COL9A1 was significantly different between the KBD and the control groups (X ² = 16.74, df = 2, P = 0.0002). Regression analysis showed that the allele “C” in SNP rs6910140 had a significant protective effect on KBD [odds ratio (OR) = 0.49, 95% confidence interval (CI) = 0.34–0.70, P = 0.0001]. The frequencies of alleles and genotypes in rs6910140 were significantly different among subjects of different KBD stages (allele: X ² = 7.82, df = 2, P = 0.02, genotype: X ² = 14.81, df = 4, P = 0.005). However, haplotype analysis did not detect any significant association between KBD and COL9A1, COL9A2 and COL9A3.

Conclusions

We observed a significant association between rs6910140 of COL9A1 and KBD, suggesting a role of COL9A1 in the development of KBD.     

A rare variant in COL11A1 is strongly associated with adult height in Chinese Han population

Human height is a highly heritable trait in which multiple genes are involved. Recent genome-wide association studies(GWASs) have identified that COL11A1 is an important susceptibility gene for human height. To determine whether the variants of COL11A1 are associated with adult and children height,we analyzed splicing and coding single-nucleotide variants across COL11A1 through exome-targeted sequencing and two validation stages with a total 20,426 Chinese Han samples. A total of 105 variants were identified by exome-targeted sequencing, of which 30 SNPs were located in coding region. The strongest association signal was chr1_103380393 with P value of 4.8 * 10~(-7). Chr1_103380393 also showed nominal significance in the validation stage(P = 1.21 * 10~(-6)). Combined analysis of 16,738 samples strengthened the original association of chr1_103380393 with adult height(P_(combined)= 3.1 * 10~(-8)), with an increased height of 0.292sd(standard deviation) per G allele(95% CI:0.19-0.40). There was no evidence(P = 0.843) showing that chr1_103380393 altered child height in 3688 child samples. Only the group of 12-15 years showed slight significance with P value of 0.0258.This study firstly shows that genetic variants of COL11A1 contribute to adult height in Chinese Han population but not to children height, which expand our knowledge of the genetic factors underlying height variation and the biological regulation of human height.     

Novel Mutations in the WNT1, TMEM38B,P4HB,and PLS3 Genes in Four Unrelated Chinese Families With Osteogenesis Imperfecta

Objective: Osteogenesis imperfecta (OI) is a group of heritable fragile bone diseases, and the majority are caused by pathogenic variants in the COL1A1 and COL1A2 genes. We sought to identify the genetic causes and phenotypes of OI in Chinese patients without COL1A1 or COL1A2 mutations.Methods: Twenty-three patients who were diagnosed with sporadic OI but did not carry COL1A1/2 mutations were recruited, and their genomic DNA was analyzed using targeted next-generation sequencing of rare OI-related genes. The resulting damaging mutations in the probands and their parents were verified using Sanger sequencing. Moreover, the efficacy of long-term bisphosphonate treatment was evaluated in proband 1.Results: Compound heterozygous variants in the WNT1 and TMEM38B genes were identified in proband 1 and proband 2, respectively. A heterozygous mutation in the P4HB gene was identified in proband 3, and a hemizygous mutation in PLS3 was identified in proband 4. The unaffected parents of the probands (except the father of proband 4) with mutations in the WNT1, TMEM38B, and PLS3 genes were heterozygous carriers of each of the variants, respectively. Notably, proband 3 had the characteristic exophthalmos, flat nasal bridge and flat, wide forehead. None of the patients presented with dentinogenesis imperfecta or hearing loss. Furthermore, bisphosphonates exerted beneficial effects on proband 1, who carried the WNT1 mutations, by increasing bone mineral density Z-score, reshaping the compressed vertebrae and decreasing the fracture risk.Conclusion: We identified novel mutations and expanded the spectrum of phenotypes and genotypes of the extremely rare disorder OI.Abbreviations: BMD = bone mineral density; MIM = Mendelian Inheritance in Man; OI = osteogenesis imperfecta; PDI = protein disulfide isomerase     

COL4A2 mutations impair COL4A1 and COL4A2 secretion and cause hemorrhagic stroke

Collagen, type IV, alpha 1 (COL4A1) and alpha 2 (COL4A2) form heterotrimers and are abundant components of basement membranes, including those of the cerebral vasculature. COL4A1 mutations are an increasingly recognized cause of multisystem disorders, including highly penetrant cerebrovascular disease and intracerebral hemorrhage (ICH). Because COL4A1 and COL4A2 are structurally and functionally associated, we hypothesized that variants in COL4A2 would also cause ICH. We sequence COL4A2 in 96 patients with ICH and identify three rare, nonsynonymous coding variants in four patients that are not present in a cohort of 144 ICH-free individuals. All three variants change evolutionarily conserved amino acids. Using a cellular assay, we show that these putative mutations cause intracellular accumulation of COL4A1 and COL4A2 at the expense of their secretion, which supports their pathogenecity. Furthermore, we show that Col4a2 mutant mice also have completely penetrant ICH and that mutations in mouse and human lead to retention of COL4A1 and COL4A2 within the endoplasmic reticulum (ER). Importantly, two of the three putative mutations found in patients trigger ER stress and activate the unfolded protein response. The identification of putative COL4A2 mutations that might contribute to ICH in human patients provides insight into the pathogenic mechanisms of this disease. Our data suggest that COL4A2 mutations impair COL4A1 and COL4A2 secretion and can also result in cytotoxicity. Finally, our findings suggest that, collectively, mutations in COL4A1 and COL4A2 contribute to sporadic cases of ICH.     

Large-scale gene-centric analysis identifies novel variants for coronary artery disease

Coronary artery disease (CAD) has a significant genetic contribution that is incompletely characterized. To complement genome-wide association (GWA) studies, we conducted a large and systematic candidate gene study of CAD susceptibility, including analysis of many uncommon and functional variants. We examined 49,094 genetic variants in ∼2,100 genes of cardiovascular relevance, using a customised gene array in 15,596 CAD cases and 34,992 controls (11,202 cases and 30,733 controls of European descent; 4,394 cases and 4,259 controls of South Asian origin). We attempted to replicate putative novel associations in an additional 17,121 CAD cases and 40,473 controls. Potential mechanisms through which the novel variants could affect CAD risk were explored through association tests with vascular risk factors and gene expression. We confirmed associations of several previously known CAD susceptibility loci (eg, 9p21.3:p<10⁻³³; LPA:p<10⁻¹⁹; 1p13.3:p<10⁻¹⁷) as well as three recently discovered loci (COL4A1/COL4A2, ZC3HC1, CYP17A1:p<5×10⁻⁷). However, we found essentially null results for most previously suggested CAD candidate genes. In our replication study of 24 promising common variants, we identified novel associations of variants in or near LIPA, IL5, TRIB1, and ABCG5/ABCG8, with per-allele odds ratios for CAD risk with each of the novel variants ranging from 1.06–1.09. Associations with variants at LIPA, TRIB1, and ABCG5/ABCG8 were supported by gene expression data or effects on lipid levels. Apart from the previously reported variants in LPA, none of the other ∼4,500 low frequency and functional variants showed a strong effect. Associations in South Asians did not differ appreciably from those in Europeans, except for 9p21.3 (per-allele odds ratio: 1.14 versus 1.27 respectively; P for heterogeneity = 0.003). This large-scale gene-centric analysis has identified several novel genes for CAD that relate to diverse biochemical and cellular functions and clarified the literature with regard to many previously suggested genes.     

Mutation characteristics in type I collagen genes in Chinese patients with osteogenesis imperfecta

Osteogenesis imperfecta is normally caused by an autosomal dominant mutation in the type I collagen genes COL1A1 and COL1A2. The severity of osteogenesis imperfecta varies, ranging from perinatal lethality to a very mild phenotype. Although there have been many reports of COL1A1 and COL1A2 mutations, few cases have been reported in Chinese people. We report on five unrelated families and three sporadic cases. The mutations were detected by PCR and direct sequencing. Four mutations in COL1A1 and one in COL1A2 were found, among which three mutations were previously unreported. The mutation rates of G>C at base 128 in intron 31 of the COL1A1 gene and G>A at base 162 in intron 30 of the COL1A2 gene were higher than normal. The patients' clinical characteristics with the same mutation were variable even in the same family. We conclude that mutations in COL1A1 and COL1A2 also have an important role in osteogenesis imperfecta in the Chinese population. As the Han Chinese people account for a quarter of the world's population, these new data contribute to the type I collagen mutation map.     

Association of ATM and BMI‐1 genetic variation with breast cancer risk in Han Chinese

We tested the hypothesis that genetic variation in ATM and BMI‐1 genes can alter the risk of breast cancer through genotyping 6 variants among 524 breast cancer cases and 518 cancer‐free controls of Han nationality. This was an observational, hospital‐based, case–control association study. Analyses of single variant, linkage, haplotype, interaction and nomogram were performed. Risk was expressed as odds ratio (OR) and 95% confidence interval (CI). All studied variants were in the Hardy‐Weinberg equilibrium and were not linked. The mutant allele frequencies of rs1890637, rs3092856 and rs1801516 in ATM gene were significantly higher in cases than in controls (P = .005, <.001 and .001, respectively). Two variants, rs1042059 and rs201024480, in BMI‐1 gene were low penetrant, with no detectable significance. After adjustment, rs189037 and rs1801516 were significantly associated with breast cancer under the additive model (OR: 1.37 and 1.52, 95% CI: 1.10‐1.71 and 1.14‐2.04, P: .005 and .005, respectively). In haplotype analysis, haplotypes A‐C‐G‐G (in order of rs189037, rs3092856, rs1801516 and rs373759) and A‐C‐A‐A in ATM gene were significantly associated with 1.98‐fold and 6.04‐fold increased risk of breast cancer (95% CI: 1.36‐2.90 and 1.65‐22.08, respectively). Nomogram analysis estimated that the cumulative proportion of 3 significant variants in ATM gene was about 12.5%. Our findings collectively indicated that ATM gene was a candidate gene in susceptibility to breast cancer in Han Chinese.     

An LRP8 variant is associated with familial and premature coronary artery disease and myocardial infarction

Our previous genomewide linkage scan of 428 nuclear families (GeneQuest) identified a significant genetic susceptibility locus for premature myocardial infarction (MI) on chromosome 1p34-36. We analyzed candidate genes in the locus with a population-based association study involving probands with premature coronary artery disease (CAD) and/or MI from the GeneQuest families (381 cases) and 560 controls without stenosis detectable by coronary angiography. A nonconservative substitution, R952Q, in LRP8 was significantly associated with susceptibility to premature CAD and/or MI by use of both population-based and family-based designs. Three additional white populations were used for follow-up replication studies: another independent cohort of CAD- and/or MI-affected families (GeneQuest II: 441 individuals from 22 pedigrees), an Italian cohort with familial MI (248 cases) and 308 Italian controls, and a separate Cleveland GeneBank cohort with sporadic MI (1,231 cases) and 560 controls. The association was significantly replicated in two independent populations with a family history of CAD and/or MI, the GeneQuest II family-based replication cohort and the Italian cohort, but not in the population with sporadic disease. The R952Q variant of LRP8 increased activation of p38 mitogen-activated protein kinase by oxidized low-density lipoprotein. This extensive study, involving multiple independent populations, provides the first evidence that genetic variants in LRP8 may contribute to the development of premature and familial CAD and MI.     

Investigation of the 1758G>C and 2880A>G variants within the NCOA3 gene in a breast cancer affected Australian population

NCOA3 is a known low to moderate-risk breast cancer susceptibility gene, amplified in 5-10% and over expressed in about 60% of breast tumours. Additionally, this over expression is associated with Tamoxifen resistance and poor prognosis. Previously, two variants of NCOA3, 1758G>C and 2880A>G have been associated with breast cancer in two independent populations. Here we assessed the influence of the two NCOA3 variants on breast cancer risk by genotyping an Australian case-control study population. 172 cases and 178 controls were successfully genotyped for the 1758G>C variant and 186 cases and 182 controls were successfully genotyped for the 2880A>G variant using high-resolution melt analysis (HRM). The genotypes of the 1758G>C variant were validated by sequencing. χ(2) tests were performed to determine if significant differences exist in the genotype and allele frequencies between the cases and controls. χ(2) analysis returned no statistically significant difference (p>0.05) for genotype frequencies between cases and controls for 1758G>C (χ(2)=0.97, p=0.6158) or 2880A>G (χ(2)=2.09, p=0.3516). Similarly, no statistical difference was observed for allele frequencies for 1758G>C (χ(2)=0.07, p=0.7867) or 2880A>G (χ(2)=0.04, p=0.8365). Haplotype analysis of the two SNPs also showed no difference between the cases and the controls (p=0.9585). Our findings in an Australian Caucasian population composed of breast cancer sufferers and an age matched control population did not support the findings of previous studies demonstrating that these markers play a significant role in breast cancer susceptibility. Here, no significant difference was detected between breast cancer patients and healthy matched controls by either the genotype or allele frequencies for the investigated variants (all p ≥ 0.05). While an association of the two variants and breast cancer was not detected in our case-control study population, exploring these variants in a larger population of the same kind may obtain results in concordance with previous studies. Given the importance of NCOA3 and its involvement in biological processes involved in breast cancer and the possible implications variants of the gene could have on the response to Tamoxifen therapy, NCOA3 remains a candidate for further investigations.     

A Genome-Wide Investigation of Copy Number Variation in Patients with Sporadic Brain Arteriovenous Malformation

Background

Brain arteriovenous malformations (BAVM) are clusters of abnormal blood vessels, with shunting of blood from the arterial to venous circulation and a high risk of rupture and intracranial hemorrhage. Most BAVMs are sporadic, but also occur in patients with Hereditary Hemorrhagic Telangiectasia, a Mendelian disorder caused by mutations in genes in the transforming growth factor beta (TGFβ) signaling pathway.

Methods

To investigate whether copy number variations (CNVs) contribute to risk of sporadic BAVM, we performed a genome-wide association study in 371 sporadic BAVM cases and 563 healthy controls, all Caucasian. Cases and controls were genotyped using the Affymetrix 6.0 array. CNVs were called using the PennCNV and Birdsuite algorithms and analyzed via segment-based and gene-based approaches. Common and rare CNVs were evaluated for association with BAVM.

Results

A CNV region on 1p36.13, containing the neuroblastoma breakpoint family, member 1 gene (NBPF1), was significantly enriched with duplications in BAVM cases compared to controls (P = 2.2×10⁻⁹); NBPF1 was also significantly associated with BAVM in gene-based analysis using both PennCNV and Birdsuite. We experimentally validated the 1p36.13 duplication; however, the association did not replicate in an independent cohort of 184 sporadic BAVM cases and 182 controls (OR = 0.81, P = 0.8). Rare CNV analysis did not identify genes significantly associated with BAVM.

Conclusion

We did not identify common CNVs associated with sporadic BAVM that replicated in an independent cohort. Replication in larger cohorts is required to elucidate the possible role of common or rare CNVs in BAVM pathogenesis.