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.

Figure 1. Characterization of 16p13.1 duplications in individuals with thoracic aortic aneurysms and dissections.

(A) The extent of 16p13.1 duplications in controls (green), the discovery cohort (blue) and the replication cohort (black) is shown. The scale is in megabases. The common duplicated region that is spanned by all CNVs is boxed. Below is a schematic of the 16p13.1-p12.3 region, which includes the location of genes and low-copy repeats (LCR, arrows).

Figure 2. Segregation of the 16p13.1 chromosomal duplication in patients with familial inheritance of thoracic aortic aneurysms and dissections.

Circles indicate females; squares indicate males. Pedigrees of families TAA337 and TAA499 are shown, and the legend indicates the diseases and the presence or absence of the 16p13.1 duplication in the family members.

Figure 3. Pathological abnormalities and MYH11 expression levels in aortic tissue associated with 16p13.1 duplication in patients with staad.

(A) Movat staining of aortic media from a 16p13.1 duplication patient shows medial degeneration characterized by proteoglycan accumulation (stained blue), loss and fragmentation of elastic fibers (stained black) and an acute aortic dissection (arrowhead) when compared with a control aorta. Some of the arteries in the vasa vasorum of the patients with 16p13.1 duplication showed increased size and thickness (arrows). Smooth muscle cell (SMC) alpha-actin staining of the vasa vasorum indicated that increased thickness of vasa vasorum was due to increased SMCs in the medial layer. (B) Quantitative real-time PCR assays (Q-PCR) of MYH11 expression levels in ascending aortic tissues from STAAD patients with and without 16p13.1 duplications and control aortic tissues indicated that MYH11 message levels were significantly increased in patients with 16p13.1 duplication (n = 4), compared to those of patients without 16p13.1 duplication (n = 6) or to controls (n = 5). The relative MYH11 mRNA expression was determined by Q-PCR and normalized to either calponin-1 (CNN1) or GAPDH.