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J Thorac Cardiovasc Surg 2006;131:1301-1305
© 2006 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Bicuspid aortic valve and ascending aortic aneurysm are not associated with germline or somatic homeobox NKX2-5 gene polymorphism in 19 patients

^a Division of Cardiovascular Surgery, Mayo Clinic, Rochester, Minn
^b Department of Surgery, Mayo Clinic, Rochester, Minn
^c Division of Orthopedic Research, Mayo Clinic, Rochester, Minn

Received for publication November 7, 2005; revisions received January 5, 2006; accepted for publication January 25, 2006.

^_* Address for reprints: Thoralf M. Sundt III, MD, Division of Cardiovascular Surgery, Mayo Clinic, 200 First St SW, Rochester, MN 55905 (Email: Sundt.Thoralf{at}mayo.edu).

BACKGROUND: Bicuspid aortic valve is the most common congenital anomaly, occurring in 1% to 2% of the population. It is the most common reason for aortic valve replacement, and such individuals are at significantly increased risk of aortic complications. Despite the clinical significance of bicuspid aortic valve, its genetic basis remains unclear. The homeobox gene NKX2-5 occupies a central position in the hierarchy of cardiac determinants, and mutations in this gene are associated with bicuspid aortic valve in mice. We therefore investigated the presence of mutations in NKX2-5 among patients with bicuspid aortic valve and associated aneurysm.

METHODS: Germline DNA was extracted from peripheral blood leukocytes and somatic DNA from diseased aortic tissues of 19 patients with bicuspid aortic valve and associated aortic aneurysm. Three patients with trileaflet aortic valve and aneurysm served as control subjects. The entire NKX2-5 coding sequence, including intron-exon boundaries, was screened for mutation by means of polymerase chain reaction, followed by DNA sequencing.

RESULTS: Direct sequencing revealed a change in somatic (aortic) DNA 239AG, leading to synonymous amino acid alteration of Glu21Glu in one patient with bicuspid aortic valve and 1 control subject. There were no other alterations detected in the coding regions of germline or somatic genes. A known polymorphic change in the 3' untranslated region adjacent to exon 2 was detected in both bicuspid aortic valve and control samples. Discrepancies between germline and somatic DNA sequences were observed.

CONCLUSION: Our study fails to demonstrate an association between bicuspid aortic valve and NKX2-5 mutation, as has been seen in mice. Our findings support the importance of sequencing somatic, as well as germline, DNA.