Systematische Identifizierung von Krankheitsgenen bei nicht-syndromalen orofazialen Spalten/Lippen-Kiefer-Gaumenspalten
Zusammenfassung der Projektergebnisse
Non-syndromic cleft lip with or without cleft palate (NSCL/P) and nonsyndromic cleft palate only (NSCPO) are amongst the most common congenital malformations worldwide. Both phenotypes have a multifactorial etiology involving both genetic and environmental components. Although there is already evidence for the involvement of multiple loci and genes in the development of nonsyndromic orofacial clefts, the genetic backgrounds of these two subtypes of orofacial clefting still await ultimate elucidation. By analyzing a large and well-characterized NSCL/P sample of Central European origin, our project so far focussed at the identification of genes underlying the aetiology of NSCL/P. The knowledge about these genes will give novel insights into the molecular basis of mid-face development, and hopefully also for NSCPO. We managed to recruit a large and well-characterized sample of Central European patients/families with NSCL/P or NSCPOs. At present (July 2012), DNA samples of 1076 affected persons from 862 family units and 1,076 DNA samples from controls (blood donors) are available. 470 family units of Central European origin were being collected in the period covered by the report. Patient recruiting and phenotype documentation was done with the aid of a standardized questionnaire. In the course of the project we were able to report on a novel key susceptibility locus for NSCL/P at chromosome 8q24.21 which was detected by a GWAS in 224 cases and 383 controls. The fact that this finding has meanwhile been replicated in numerous ethnicities, and given the comparably high odds ratios, this result constitutes a major breakthrough in cleft research. However, further research is needed to detect the causal variant(s) at this locus. In a second step, we performed a GWAS in an enlarged sample of 401 patients and 1323 controls. Candidate SNPs were replicated in an independent European sample of 793 NSCL/P trios. By these means we detected two new loci (17q22, 10q25.3) that reach genome-wide significance, and which harbour promising candidate genes based on functional experiments (noggin precursor (NOG) and ventral anterior homeobox 1 (VAX1). We conducted the first meta-analyses for nonsyndromic cleft lip with or without cleft palate (NSCL/P) using data from the two largest genome-wide association studies published to date. We confirmed all previously identified loci, and identified six additional susceptibility regions (1p36, 2p21, 3p11.1, 8q21.3, 13q31.1, and 15q22). Analysis of phenotypic variability identified the first specific genetic risk-factor for nonsyndromic cleft lip plus cleft palate at chromosome 13q31.1. In addition to the GWAS, we also conducted several candidate gene studies in our NSCL/P sample. These studies, genes for which were chosen based on literature and functional data, provided significant evidence for a causative role of MYH9 in NSCL/P development, and confirmed the involvement of the IRF6-variant rs642961 in the etiology of NSCL/P. An indepth investigation of SUMO1 did not reveal significant findings, demonstrating that this gene does probably not contribute to the development of NSCL/P in Central Europeans. In conclusion, our NSCL/P sample – that we plan to enlarge even further – and the results of the genome-wide association scan are an excellent starting point to identify novel genes underlying the aetiology of isolated orofacial clefts.
Projektbezogene Publikationen (Auswahl)
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(2008) Family-based association study of the MTHFR polymorphism C677T in patients with nonsyndromic cleft lip and palate from central Europe. Cleft Pal Craniofac J.; 45(3):267-271
Reutter H, Birnbaum S, Lacava AD, Mende M, Henschke H, Bergé S, Braumann B, Lauster C, Schiefke F, Wenghoefer M, Saffar M, Reich R, Scheer M, Kramer F-J, Knapp M and Mangold E
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(2008) TGFB3 displays parent-of-origin effects among central Europeans with nonsyndromic cleft lip and palate. J Hum Genet; 53(7):656-661
Reutter H, Birnbaum S, Mende M, Lauster C, Schmidt G, Henschke H, Saffar M, Martini M, Lauster R, Schiefke F, Reich RH, Braumann B, Scheer M, Knapp M, Nöthen MM, Kramer F- J, Mangold E
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(2009) Further evidence for the involvement of MYH9 in the etiology of non-syndromic cleft lip with or without cleft palate. Eur J of Or Sci; 117:200-203
Birnbaum S, Reutter H, Mende M, de Assis NA, Diaz-Lacava A, Herms S, Scheer M, Lauster C, Braumann B, Schmidt G, Martini M, Hemprich A, Pötzsch S, Knapp M, Nöthen MM, Kramer F-J, Mangold E.
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(2009) IRF6 gene variants in Central European patients with non-syndromic cleft lip with or without cleft palate. Eur J Or Sci; 117:766–769
Birnbaum S, Ludwig KU, Reutter H, Herms S, Almeida de Assis N, Diaz-Lacava A, Barth S, Lauster C, Schmidt G, Scheer M, Saffar M, Martini M, Reich RH, Schiefke F, Hemprich A, Pötzsch S, Pötzsch B, Wienker TF, Hoffmann P, Knapp M, Kramer F-J, Nöthen MM, Mangold E
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(2009) Key susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24. Nat Genet; 41:473-477
Birnbaum S, Ludwig KU, Reutter H, Herms S, Steffens M, Rubini M, Baluardo C, Ferrian M, Almeida De Assis N, Alblas MA, Barth S, Freudenberg J, Lauster C, Schmidt G, Scheer M, Braumann B, Bergé SJ, Reich RH, Schiefke F, Hemprich A, Pötzsch S, Steegers- Theunissen RP, Pötzsch B, Moebus S, Horsthemke B, Kramer F-J, Wienker TF, Mossey PA, Propping P, Cichon S, Hoffmann P, Knapp M, Nöthen MM, Mangold E
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(2009) Replication of novel susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 8q24 in Estonian and Lithuanian patients. Am J Med Genet A;149A(11):2551-2253
Nikopensius T, Ambrozaityte L, Ludwig KU, Birnbaum S, Jagomägi T, Saag M, Matuleviciene A, Linkeviciene L, Herms S, Knapp M, Hoffmann P, Nöthen MM, Kucinskas V, Metspalu A, Mangold E
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(2010) Genetic risk factors for nonsyndromic cleft lip with or without cleft palate in a Mesoamerican population: Evidence for IRF6 and variants at 8q24 and 10q25. Birth Def Res, Part A; 88: 535–537
Rojas-Martinez A, Reutter H, Chacon-Camacho O, Leon-Cachon RBR, Munoz-Jimenez SG, Nowak S, Becker J, Herberz R, Ludwig KU, Paredes-Zenteno M, Arizpe-Cantú A, Raeder S, Herms S, Ortiz-Lopez R, Knapp M, Hoffmann P, Nöthen MM, Mangold E
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(2010) Genome-wide association study identifies new susceptibility loci for non-syndromic cleft lip with or without cleft palate. Nat Genet; 42(1):24– 26
Mangold E, Ludwig KU, Birnbaum S, Baluardo C, Ferrian M, Herms S, Reutter H, Almeida de Assis N, Al Chawa T, Mattheisen M, Steffens M, Barth S, Kluck N, Paul A, Becker J, Lauster C, Schmidt G, Braumann B, Scheer M, Reich RH, Hemprich A, Pötzsch S, Blaumeiser B, Moebus S, Krawczak M, Schreiber S, Meitinger T, Wichmann HE, Steegers- Theunissen RP, Kramer F-J, Cichon S, Propping P, Wienker TF, Knapp M, Rubini M, Mossey PA, Hoffmann P, Nöthen MM
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(2010) Susceptibility locus for nonsyndromic cleft lip with or without cleft palate on chromosome 10q25 confers risk in Estonian patients. Eur J Or Sci; 118(3):317-319
Nikopensius T, Birnbaum S, Ludwig KU, Jagomägi T, Saag M, Herms S, Knapp M, Hoffmann P, Nöthen MM, Metspalu A, Mangold E
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(2011) Breakthroughs in the genetics of orofacial clefting. Trends Mol Med. 17(12):725-733
Mangold E, Ludwig KU, Nöthen MM
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(2011) FAF1, a Gene that Is Disrupted in Cleft Palate and Has Conserved Function in Zebrafish. Am J Hum Genet. 88:150-161
Ghassibe-Sabbagh M, Desmyter L, Langenberg T, Claes F, Boute O, Bayet B, Pellerin P, Hermans K, Backx L, Mansilla MA, Imoehl S, Nowak S, Ludwig KU, Baluardo C, Ferrian M, Mossey PA, Noethen M, Dewerchin M, François G, Revencu N, Vanwijck R, Hecht J, Mangold E, Murray J, Rubini M, Vermeesch JR, Poirel HA, Carmeliet P, Vikkula M
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(2011) Genetic determination of human facial morphology: links between cleft-lips and normal variation. Eur J Hum Genet. 19:1192-1197
Boehringer S, van der Lijn F, Liu F, Günther M, Sinigerova S, Nowak S, Ludwig KU, Herberz R, Klein S, Hofman A, Uitterlinden AG, Niessen WJ, Breteler MM, van der Lugt A, Würtz RP, Nöthen MM, Horsthemke B, Wieczorek D, Mangold E, Kayser M
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(2011) On the analysis of sequence data: testing for disease susceptibility loci using patterns of linkage disequilibrium. Genet Epidemiol. 2011;35:880-886
Lipman PJ, Yip WK, AlChawa T, Ludwig KU, Mangold E, Lange C
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(2011) SUMO1 as a candidate gene for nonsyndromic cleft lip with or without cleft palate: no evidence for the involvement of common or rare variants in Central European patients. Int J Pediat Otorh; 75(1):49-52
Almeida de Assis N, Nowak S, Ludwig KU, Reutter H, Vollmer J, Heilmann S, Kluck N, Lauster C, Braumann B, Reich RH, Hemprich A, Pötzsch B, Knapp M, Wienker TF, Kramer F-J, Hoffmann P, Nöthen MM, Mangold E
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(2012) Is it rare or common? Genet Epidemiol; 36(5):419-429
Adhikari K, Alchawa T, Ludwig K, Mangold E, Laird N, Lange C
