Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene

Iris A. L. M. van Rooij, Kerstin U. Ludwig, Julia Welzenbach, Nina Ishorst, Michelle Thonissen, Tessel E. Galesloot, Edwin Ongkosuwito, Stefaan J. Berge, Khalid Aldhorae, Augusto Rojas-Martinez, Lambertus A. L. M. Kiemeney, Joris Robert Vermeesch, Han Brunner, Nel Roeleveld, Koen Devriendt, Titiaan Dormaar, Greet Hens, Michael Knapp, Carine Carels, Elisabeth Mangold*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

11 Citations (Web of Science)


Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 x 10( -7)). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10824.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.

Original languageEnglish
Article number1023
Number of pages14
Issue number12
Publication statusPublished - 7 Dec 2019


  • congenital malformation
  • orofacial cleft
  • cleft lip with or without cleft palate
  • genome-wide association study
  • IRF6
  • FOXE1

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