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

J Med Genet. 2018 Jul;55(7):449-458. doi: 10.1136/jmedgenet-2017-105110. Epub 2018 Mar 2.


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.

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

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Abnormalities, Multiple / diagnosis
  • Abnormalities, Multiple / genetics*
  • Abnormalities, Multiple / physiopathology
  • Adult
  • Brain / abnormalities*
  • Brain / physiopathology
  • Child, Preschool
  • Cleft Lip / diagnosis
  • Cleft Lip / genetics*
  • Cleft Lip / physiopathology
  • Cleft Palate / diagnosis
  • Cleft Palate / genetics*
  • Cleft Palate / physiopathology
  • DNA-Binding Proteins / genetics*
  • Exome Sequencing / methods
  • Female
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics*
  • Male
  • Mutation / genetics
  • Pedigree
  • Polymorphism, Single Nucleotide / genetics
  • T-Box Domain Proteins / genetics*
  • Transcription Factors / genetics*
  • Tumor Suppressor Proteins / genetics*
  • Young Adult


  • DNA-Binding Proteins
  • GRHL3 protein, human
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • T-Box Domain Proteins
  • TBX1 protein, human
  • TP63 protein, human
  • Transcription Factors
  • Tumor Suppressor Proteins

Supplementary concepts

  • Orofacial Cleft 1
  • Van der Woude syndrome 2