SUMO1 as a candidate gene for non-syndromic cleft lip with or without cleft palate: No evidence for the involvement of common or rare variants in Central European patients Nilma Almeida de Assis a , Stefanie Nowak a , Kerstin U. Ludwig a,b , Heiko Reutter a , Jennifer Vollmer a,b , Stefanie Heilmann a,b , Nadine Kluck a,b , Carola Lauster c , Bert Braumann d , Rudolf H. Reich e , Alexander Hemprich f , Michael Knapp g , Thomas F. Wienker g , Franz-Josef Kramer h , Per Hoffmann a,b , Markus M. No ¨ then a,b , Elisabeth Mangold a, * a Institute of Human Genetics, University of Bonn, Sigmund-Freud-Straße 25, 53127 Bonn, Germany b Department of Genomics, Life and Brain Center, University of Bonn, Bonn, Germany c Department of Cleft Lip and Cleft Palate Surgery, Humboldt University of Berlin, Berlin, Germany d Department of Orthodontics, University of Cologne, Cologne, Germany e Department of Oral and Maxillo-Facial-Plastic Surgery, University of Bonn, Bonn, Germany f Department of Oral and Maxillo-Facial Surgery, University of Leipzig, Leipzig, Germany g Institute of Medical Biometry, Informatics, and Epidemiology, University of Bonn, Bonn, Germany h Department of Oral and Maxillofacial Surgery, University of Go ¨ttingen, Go ¨ttingen, Germany 1. Introduction Orofacial clefting is the most common congenital craniofacial disorder. Approximately 1 of every 600 newborns worldwide is affected [1]. The two most common forms of clefting are cleft-lip with or without cleft palate (CL/P) and cleft palate only (CPO). These may occur as part of a complex malformation syndrome or as isolated anomalies. Approximately 70% of all CL/P cases are non-syndromic (NSCL/P), in contrast to only around 50% of all CPO cases (NSCPO). Although most epidemiological research has suggested that NSCL/P and NSCPO are distinct entities, there is some evidence of an etiological overlap [2–4]. Several molecular genetic studies have been performed to elucidate the genetic background of non-syndromic orofacial clefting. Proven suscep- tibility loci for NSCL/P include one gene (IRF6, interferon regulatory factor 6) and five defined genomic regions (1p22.1, 8q24, 17q22, 10q25, 20q12) [5–9]. No consistent results have been obtained to date for NSCPO. International Journal of Pediatric Otorhinolaryngology 75 (2011) 49–52 ARTICLE INFO Article history: Received 25 July 2010 Accepted 2 October 2010 Available online 1 November 2010 Keywords: Cleft lip and palate Association study ABSTRACT Objective: Studies in mice and humans have suggested that SUMO1, which codes for the small ubiquitin- related modifier 1 (SUMO1), is a promising candidate gene for non-syndromic cleft lip with or without cleft palate (NSCL/P). To investigate the possible involvement of this gene in NSCL/P patients from Central Europe, we performed: (i) a case control association study, and (ii) a resequencing study. Methods: Genotyping and the subsequent single marker and haplotype association analyses were performed for 413 NSCL/P patients and 412 controls. A total of 17 tagging single-nucleotide polymorphisms (SNPs) were used. In the resequencing study, the complete coding region and splice sites were sequenced in 65 index patients from multiply affected families. Results: One of the 17 tested SNPs (rs16838917) had a borderline significant P-value of 0.0416 in the single-marker association analysis. However, this result did not withstand correction for multiple testing (P corr = 0.707). No association was observed for any haplotypic marker combination. Sequencing failed to identify any novel rare sequence variants. Conclusions: The results of the present study do not support the hypothesis that common or rare variants in SUMO1 play a significant role in the development of NSCL/P in Central-European patients. However, smaller effects of common variants or the presence of rare high penetrance mutations in other non- investigated familial cases cannot be excluded. Further analysis of SUMO1 in independent samples from Central European and other populations is therefore warranted. ß 2010 Elsevier Ireland Ltd. All rights reserved. * Corresponding author. E-mail address: e.mangold@uni-bonn.de (E. Mangold). Contents lists available at ScienceDirect International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl 0165-5876/$ – see front matter ß 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijporl.2010.10.005