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(Circulation. 2007;115:1912-1920.)
© 2007 American Heart Association, Inc.

Valvular Heart Disease

Mutations in FOXC2 Are Strongly Associated With Primary Valve Failure in Veins of the Lower Limb

Russell H. Mellor, PhD; Glen Brice, BSc; Anthony W.B. Stanton, PhD; Jane French, MSc; Alberto Smith, PhD; Steve Jeffery, PhD; J. Rodney Levick, DSc, MRCP; Kevin G. Burnand, MS, FRCS; Peter S. Mortimer, MD, FRCP

From Cardiac & Vascular Sciences (Dermatology) (R.H.M, A.W.B.S, P.S.M.), Clinical Genetics (G.B.), Clinical Developmental Sciences (S.J.), and Physiology (J.R.L.), St George’s, University of London, London, UK; Vascular Laboratory (J.F.), St George’s Hospital, London, UK; and Department of Academic Surgery (A.S, K.G.B.), St Thomas’ Hospital, London, UK. Dr Mellor, G. Brice, Dr Smith, Prof Jeffery, Prof Burnand, and Prof Mortimer represent the Lymphoedema Research Consortium.

Correspondence to Professor P.S. Mortimer, Cardiac & Vascular Sciences (Dermatology Unit), St George’s, University of London, Cranmer Terrace, London, SW17 0RE, UK. E-mail mortimer{at}sgul.ac.uk

Received June 6, 2006; accepted January 5, 2007.

Background— Mutations in the FOXC2 gene cause lymphedema distichiasis, an inherited primary lymphedema in which a significant number of patients have varicose veins. Because lymphedema distichiasis is believed to be caused by lymphatic valve failure (reflux), and FOXC2 is highly expressed on venous valves in mouse embryos, we tested the hypothesis that FOXC2 mutations may be linked to venous valve failure and reflux.

Methods and Results— The venous system of the leg was investigated with Duplex ultrasound. Pathological reflux was recorded by color Duplex ultrasound in all 18 participants with a FOXC2 mutation, including 3 without lymphedema. Every participant with a mutation in FOXC2 showed reflux in the great saphenous vein (n=18), compared with only 1 of 12 referents (including 10 family members; P<0.0001, Fisher exact test). Deep vein reflux was recorded in 14 of 18 participants.

Conclusions— FOXC2 is the first gene in which mutations have been strongly associated with primary venous valve failure in both the superficial and deep veins in the lower limb. This gene appears to be important for the normal development and maintenance of venous and lymphatic valves.

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