Recurrent Chromosome 16p13.1 Duplications Are a Risk Factor for Aortic Dissections

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.

Application of custom-designed oligonucleotide array CGH in 145 patients with autistic spectrum disorders

“…30 However, other reports associated this CNV with a variety of neuropsychiatric and neurobehavioral disorders, including autism, schizophrenia, intellectual disabilities, cognitive impairment, attention deficit hyperactivity disorder, and epilepsy, as well as congenital heart defects, skeletal manifestations, and thoracic aortic aneurysms and dissections. [31][32][33][34][35][36][37] We suggest that this duplication may contribute to the autistic features seen in patient 7.…”

Copy number analysis of 413 isolated talipes equinovarus patients suggests role for transcriptional regulators of early limb development

“…Deletions and duplications of chromosome 16p13.1 have been implicated in a variety of neuropsychiatric disorders, 38 thoracic aortic aneurysms and dissection, 39 as well as skeletal manifestations including hypermobility, craniosynostosis, and polydactyly. 40 We identified an enrichment of chromosome 16p13.1 CNVs (P ¼ 0.036), consisting of one deletion and three duplications in our isolated talipes equinovarus cohort and a single duplication in our bipolar controls.…”

Overexpression of Smooth Muscle Myosin Heavy Chain Leads to Activation of the Unfolded Protein Response and Autophagic Turnover of Thick Filament-associated Proteins in Vascular Smooth Muscle Cells

“…Recurrent copy number variants at the chromosomal locus 16p13.1 have been implicated in the pathogenesis of neuropsychiatric disorders, and we have recently reported that duplications but not deletions of this same locus are enriched 11-fold in patients with sporadic thoracic aortic aneurysms and dissections (TAAD) 2 (3). Although the size of the duplication can vary, nine genes are commonly duplicated in all TAAD patients, including MYH11.…”