title: 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.
authors.affiliation: Department of Internal Medicine, University of Texas Health Science Center at Houston, Houston, Texas, USA.
authors.forename: Shao-Qing
authors.initials: SQ
authors.lastname: Kuang
authors.forename: Dong-Chuan
authors.initials: DC
authors.lastname: Guo
authors.forename: Siddharth K
authors.initials: SK
authors.lastname: Prakash
authors.forename: Merry-Lynn N
authors.initials: ML
authors.lastname: McDonald
authors.forename: Ralph J
authors.initials: RJ
authors.lastname: Johnson
authors.forename: Min
authors.initials: M
authors.lastname: Wang
authors.forename: Ellen S
authors.initials: ES
authors.lastname: Regalado
authors.forename: Ludivine
authors.initials: L
authors.lastname: Russell
authors.forename: Jiu-Mei
authors.initials: JM
authors.lastname: Cao
authors.forename: Callie
authors.initials: C
authors.lastname: Kwartler
authors.forename: Kurt
authors.initials: K
authors.lastname: Fraivillig
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Coselli
authors.forename: Hazim J
authors.initials: HJ
authors.lastname: Safi
authors.forename: Anthony L
authors.initials: AL
authors.lastname: Estrera
authors.forename: Suzanne M
authors.initials: SM
authors.lastname: Leal
authors.forename: Scott A
authors.initials: SA
authors.lastname: LeMaire
authors.forename: John W
authors.initials: JW
authors.lastname: Belmont
authors.forename: Dianna M
authors.initials: DM
authors.lastname: Milewicz
mesh_terms: D000328:Adult; D000368:Aged; D000784:Aortic Dissection / Q000235:genetics* / Q000473:pathology; D001011:Aorta / Q000473:pathology; D017545:Aortic Aneurysm, Thoracic / Q000235:genetics* / Q000473:pathology; D016022:Case-Control Studies; D058674:Chromosome Duplication / Q000235:genetics*; D002885:Chromosomes, Human, Pair 16 / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008875:Middle Aged; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D010375:Pedigree; D010641:Phenotype; D012307:Risk Factors
chemical_list: C509903:MYH11 protein, human; D018995:Myosin Heavy Chains