Abstract
Chromosomal deletions or reciprocal duplications of the 16p13.1 region have been implicated in a variety of neuropsychiatric disorders such as autism, schizophrenia, epilepsies, and attention-deficit hyperactivity disorder (ADHD). In this study, we investigated the association of recurrent genomic copy number variants (CNVs) with thoracic aortic aneurysms and dissections (TAAD). By using SNP arrays to screen and comparative genomic hybridization microarrays to validate, we identified 16p13.1 duplications in 8 out of 765 patients of European descent with adult-onset TAAD compared with 4 of 4,569 controls matched for ethnicity (P = 5.0×10−5, OR = 12.2). The findings were replicated in an independent cohort of 467 patients of European descent with TAAD (P = 0.005, OR = 14.7). Patients with 16p13.1 duplications were more likely to harbor a second rare CNV (P = 0.012) and to present with aortic dissections (P = 0.010) than patients without duplications. Duplications of 16p13.1 were identified in 2 of 130 patients with familial TAAD, but the duplications did not segregate with TAAD in the families. MYH11, a gene known to predispose to TAAD, lies in the duplicated region of 16p13.1, and increased MYH11 expression was found in aortic tissues from TAAD patients with 16p13.1 duplications compared with control aortas. These data suggest chromosome 16p13.1 duplications confer a risk for TAAD in addition to the established risk for neuropsychiatric disorders. It also indicates that recurrent CNVs may predispose to disorders involving more than one organ system, an observation critical to the understanding of the role of recurrent CNVs in human disease and a finding that may be common to other recurrent CNVs involving multiple genes.
Highlights
Recurrent copy number variants (CNVs) in the human genome occur in areas of the genome prone to non-allelic homologous recombination (NAHR) due to unequal crossover between large regions of highly identical segmental duplications (.10 Kb in length with .90% sequence identity) [1,2,3]
Our study suggests that recurrent duplications of 16p13.1 confer a risk for both neuropsychiatric diseases and thoracic aortic aneurysms and dissections (TAAD), a finding that may be common to other recurrent CNVs involving multiple genes
Human CNV370-Quad BeadChip) obtained from 765 unrelated sporadic thoracic aortic aneurysms and dissections (STAAD) patients of European descent over the age of 30 years (STAAD-1 cohort) were analyzed for CNVs and compared with CNVs identified from SNP array data from 4569 ethnically matched controls (Table S1) as previously reported [22]
Summary
Recurrent copy number variants (CNVs) in the human genome occur in areas of the genome prone to non-allelic homologous recombination (NAHR) due to unequal crossover between large regions of highly identical segmental duplications (.10 Kb in length with .90% sequence identity) [1,2,3]. Recurrent copy number variants (CNVs) in the human genome occur in areas of the genome prone to non-allelic homologous recombination (NAHR) due to unequal crossover between large regions of highly identical segmental duplications The short arm of chromosome 16 contains an unusually high number of interspersed segmental repeats, which lead to recurrent deletions and duplications of discrete regions such as 16p13.1. Deletions of 16p13.1 vary in size but typically involve 14.7 Mb to 16.3 Mb and have been described in a variety of complex mental disorders such as autism, mental retardation, schizophrenia, attention-deficit hyperactivity disorder (ADHD), and epilepsy [1,4,5,6,7,8]. The prevalence of reciprocal duplications of 16p13.1 is significantly increased in patients with schizophrenia and ADHD [9,10]. CNVs involving 16p13.1 are found in normal controls, which raise the question as to what determines the pathogenicity of these CNVs
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