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Original article
Whole exome sequencing identifies mutations in 10% of patients with familial non-syndromic cleft lip and/or palate in genes mutated in well-known syndromes
  1. Mirta Basha1,
  2. Bénédicte Demeer1,2,3,
  3. Nicole Revencu1,4,
  4. Raphael Helaers1,
  5. Stephanie Theys5,
  6. Sami Bou Saba6,
  7. Odile Boute7,
  8. Bernard Devauchelle8,
  9. Geneviève Francois9,
  10. Bénédicte Bayet10,
  11. Miikka Vikkula1
  1. 1Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels, Belgium
  2. 2Center for Human Genetics, CLAD nord de France, CHU Amiens, Amiens, France
  3. 3EA 4666, Université Picardie Jules Verne, Amiens, France
  4. 4Center for Human Genetics, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
  5. 5Pediatric Dentistry and Oral Care for Special Needs, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
  6. 6Department of Orthodontics and Dentofacial Orthopedics, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
  7. 7Service de génétique clinique Guy Fontaine, CHRU de Lille - Hôpital Jeanne de Flandre, Lille, France
  8. 8Service of Maxillofacial Surgery and Stomatology, CHU Amiens-Picardie, Amiens, France
  9. 9Department of Pediatrics, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
  10. 10Division of Plastic Surgery, Centre Labio-Palatin, Cliniques universitaires Saint-Luc, University of Louvain, Brussels, Belgium
  1. Correspondence to Professor Miikka Vikkula, Human Molecular Genetics, de Duve Institute, University of Louvain, Brussels 1348, Belgium; miikka.vikkula{at}


Background Oral clefts, that is, clefts of the lip and/or cleft palate (CL/P), are the most common craniofacial birth defects with an approximate incidence of ~1/700. To date, physicians stratify patients with oral clefts into either syndromic CL/P (syCL/P) or non-syndromic CL/P (nsCL/P) depending on whether the CL/P is associated with another anomaly or not. In general, patients with syCL/P follow Mendelian inheritance, while those with nsCL/P have a complex aetiology and, as such, do not adhere to Mendelian inheritance. Genome-wide association studies have identified approximately 30 risk loci for nsCL/P, which could explain a small fraction of heritability.

Methods To identify variants causing nsCL/P, we conducted whole exome sequencing on 84 individuals with nsCL/P, drawn from multiplex families (n=46).

Results We identified rare damaging variants in four genes known to be mutated in syCL/P: TP63 (one family), TBX1 (one family), LRP6 (one family) and GRHL3 (two families), and clinical reassessment confirmed the isolated nature of their CL/P.

Conclusion These data demonstrate that patients with CL/P without cardinal signs of a syndrome may still carry a mutation in a gene linked to syCL/P. Rare coding and non-coding variants in syCL/P genes could in part explain the controversial question of ‘missing heritability’ for nsCL/P. Therefore, gene panels designed for diagnostic testing of syCL/P should be used for patients with nsCL/P, especially when there is at least third-degree family history. This would allow a more precise management, follow-up and genetic counselling. Moreover, stratified cohorts would allow hunting for genetic modifiers.

  • expanded spectrum of syCL/P
  • gene
  • cleft
  • syndrome
  • mutation
  • phenotype
  • nsCL/P
  • syCL/P
  • WES
  • NGS
  • transcription factor
  • craniofacial syndrome
  • Van der Woude
  • EEC
  • 22qdel
  • tooth agenesis (oligodontia)

Statistics from


  • Contributors MB and MV prepared the manuscript. MB performed patient selection for WES, WES data analysis and validation/co-segregation of identified variants. BD, NR and BB were in charge of enrolment of subjects and collecting samples. RH helped in bioinformatic analyses of WES data. BD, NR, ST, SBS, OB, BD, GF and BB collected the clinical data. All authors contributed to re-drafting of the manuscript. MV conceived and coordinated the project and is responsible for the overall content. All authors have seen and approved the final manuscript.

  • Funding These studies were partially supported by funding from the Belgian Science Policy Office Interuniversity Attraction Poles (BELSPO-IAP) programme through the project IAP P7/43-BeMGI; BridgeIris RBC/2013-PFS-EH-11; the Fonds de la Recherche Scientifique—FNRS; CdR: J.0080.16 (all to MV). We also acknowledge the support of la Communauté française de Wallonie-Bruxelles, la Lotterie Nationale, Belgium and la région Haut de France, France. The authors thank the Genomics Platform of Université catholique de Louvain for next-generation sequencing analyses and the Foundation against Cancer, Belgium.

  • Competing interests None declared.

  • Patient consent Not required.

  • Ethics approval This study obtained ‘La Commission d’Ethique Biomédicale Hospitalo-Facultaire’ approval (2015/02NOV/572) by the medical faculty at University of Louvain, Brussels, Belgium.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Data sharing statement All data relating to the study are available within the manuscript and accompanying online supplementary files.

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