MUTATION IN BRIEF HUMAN MUTATION Mutation in Brief #728 (2004) Online © 2004 WILEY-LISS, INC. DOI: 10.1002/humu.9257 Received 5 November 2003; accepted revised manuscript 26 April 2004. Maternal MTHFR Variant Forms Increase the Risk in Offspring of Isolated Nonsyndromic Cleft Lip With or Without Cleft Palate F. Pezzetti 1 , M. Martinelli 2 , L. Scapoli 1,2 , F. Carinci 3 , A. Palmieri 1 , J. Marchesini 2 , P. Carinci 1,4 , E. Caramelli 1 , R. Rullo 5 , F. Gombos 5 , and M. Tognon 2 * 1 Institute of Histology and General Embryology, University of Bologna, Via Belmeloro 8, 40126 Bologna, Italy; 2 Department of Morphology and Embryology, Section of Histology and Embryology, University of Ferrara, Via Fossato di Mortara 64/B, 44100 Ferrara, Italy; 3 Chair of Maxillo-Facial Surgery, University of Ferrara, Corso Giovecca 203, 44100 Ferrara, Italy; 4 Centre of Molecular Genetics, CARISBO Foundation, University of Bologna, Via Belmeloro 8, 40126 Bologna, Italy; 5 Odontoiatric Clinic, S.U.N., Via S. Andrea delle Dame 6, 80100 Napoli, Italy *Correspondence to: Mauro Tognon, Ph.D., Department of Morphology and Embryology, Section of Histology and Embryology, University of Ferrara, Via Fossato di Mortara 64/B, 44100 Ferrara, Italy; Tel.: +39-0532-291538; Fax : +39-0532-291533; E-mail: tgm@unife.it Grant sponsor: Fondazione Telethon; Grant number: E.1147 Communicated by Iain McIntosh The pathogenesis of cleft lip with or without cleft palate (CL/P) is complex; its onset could be due to the interaction of various genetic and environmental factors. Recently MTHFR functional polymorphisms were found to increase the risk of this common malformation; however, this finding is still debated. We investigated 110 sporadic CL/P patients, their parents and 289 unrelated controls for c.665C>T (commonly known as 677C>T; p.Ala222Val) and c.1286A>C (known as 1298A>C; p.Glu429Ala) polymorphism in the MTHFR gene. Transmission disequilibrium test (TDT) showed no distortion in allele transmission. Nevertheless, association studies revealed significant differences in allele frequencies between mothers of CL/P patients and controls. This work supports the hypothesis that a lower MTHFR enzyme activity in pregnant women, mostly related to the c.665C>T variant form, is responsible for a higher risk of having CL/P affected offspring. © 2004 Wiley-Liss, Inc. KEY WORDS: Orofacial cleft; cleft lip with or without cleft palate; MTHFR INTRODUCTION Cleft lip with or without cleft palate (CL/P, MIM# 119530) is one of the most frequent congenital diseases (Tolarova and Cervenka, 1998), although its etiology is still under investigation. Since 20% of patients have a positive family history, genetic factors are thought to play an important role in the etiology of this birth defect (Murray, 1995; Carinci et al., 2003). The inheritance of CL/P is complex, and many models have been proposed to