Clin Genet 2010: 78: 247 – 256 Printed in Singapore. All rights reserved © 2010 John Wiley & Sons A/S CLINICAL GENETICS doi: 10.1111/j.1399-0004.2010.01375.x Short Report Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan Malik S, Kakar N, Hasnain S, Ahmad J, Wilcox ER, Naz S. Epidemiology of Van der Woude syndrome from mutational analyses in affected patients from Pakistan. Clin Genet 2010: 78: 247–256. © John Wiley & Sons A/S, 2010 Mutations in IRF6 cause Van der Woude syndrome (VWS), one of the most common syndromes associated with cleft lip (CL) with or without cleft palate (CP). The presence of pits on the lower lip of patients is the most characteristic feature of the syndrome. We have identified three novel and seven previously reported IRF6 mutations in 12 of 16 unrelated families segregating VWS from Pakistan. The three newly identified mutations include a frameshift (c.568delG) and two missense mutations c.295G>A (p.G99S) and c.1219T>C (p.S407P). Recent functional studies on IRF6 and the three-dimensional structure of IRF5 carboxy (C) terminus, a protein encoded by a paralog of IRF6, shed light on the p.S407P substitution. Additionally, the identification of the same mutations responsible for VWS in Pakistan, as reported in other global populations worldwide, marks these residues as mutational hotspots and indicates their essential role in structural stability or function of IRF6. This is the first study of VWS in Pakistan and we estimate that 1 in 100 patients with CL with or without CP (CL/P) are affected in the Pakistani population predominantly from the Punjab area. S Malik a,b , N Kakar c , S Hasnain b , J Ahmad c , ER Wilcox d and S Naz a a School of Biological Sciences, and b Department of Microbiology and Molecular Genetics, University of the Punjab, Lahore, Pakistan, c Faculty of Biotechnology and Informatics, Balochistan University of Information Technology and Management Sciences, Quetta, Pakistan, and d Department of Biology, Brigham Young University, Provo, UT, USA Key words: cleft lip – cleft palate – IRF6 mutations – Pakistan – Van der Woude syndrome Corresponding author: Sadaf Naz, School of Biological Sciences, University of the Punjab, Quaid-i-Azam Campus, Lahore 54590, Pakistan. Tel.: +92 42 9923 1819; fax: +92 42 9923 0980; e-mail: naz@sbs.pu.edu.pk Received 21 November 2009, revised and accepted for publication 4 January 2010 Orofacial clefts including cleft lip and cleft palate (CL/P) are a major structural birth defect with the worldwide incidence roughly 1 in 500–1000 births (1, 2). More than 400 syndromes include cleft lip (CL) with or without cleft palate (CP) in their etiology. Van der Woude syndrome (VWS) (MIM# 119300) is one of the most common accounting for about 2% of all cases of CL/P worldwide (3). VWS is inherited in an autosomal dominant manner and has a high-penetrance rate (96.7%) with intrafamilial and interfamilial variation of the associated phenotype. The distinctive feature of VWS is the presence of lower lip pits and/or sinuses, which are present in approximately 85% of cases. In some rare cases, a single barely visi- ble pit might be the only distinguishable feature of VWS. Other anomalies that are frequently associ- ated with VWS include hypodontia, submucous CP and bifid uvula (4). Infrequent anomalies include congenital adhesion of the jaw, narrow arched palate and ankyloglossia (tongue tie) (5). The clinical features of VWS closely resem- ble Popliteal Pterygium Syndrome (PPS; MIM# 119500). PPS is also inherited in a dominant fashion but lip pits are less common (45.6%). Additional features include skin webbing, genital abnormalities, syndactyly of fingers and/or toes, and abnormal skin around the nails. Both VWS and PPS are caused by mutations in interferon 247