Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate

Waheed Awotoye (Lead / Corresponding author), Peter A. Mossey, Jacqueline B. Hetmanski, Lord J. J. Gowans, Mekonen A. Eshete, Wasiu L. Adeyemo, Azeez Alade, Erliang Zeng, Olawale Adamson, Thirona Naicker, Deepti Anand, Chinyere Adeleke, Tamara Busch, Mary Li, Aline Petrin, Babatunde S. Aregbesola, Ramat O. Braimah, Fadekemi O. Oginni, Ayodeji O. Oladele, Abimbola OladayoSami Kayali, Joy Olotu, Mohaned Hassan, John Pape, Peter Donkor, Fareed K. N. Arthur, Solomon Obiri-Yeboah, Daniel K. Sabbah, Pius Agbenorku, Gyikua Plange-Rhule, Alexander Acheampong Oti, Rose A. Gogal, Terri H. Beaty, Margaret Taub, Mary L. Marazita, Michael J. Schnieders, Salil A. Lachke, Adebowale A. Adeyemo, Jeffrey C. Murray, Azeez Butali (Lead / Corresponding author)

Research output: Contribution to journalArticlepeer-review

13 Citations (Scopus)
48 Downloads (Pure)


The majority (85%) of nonsyndromic cleft lip with or without cleft palate (nsCL/P) cases occur sporadically, suggesting a role for de novo mutations (DNMs) in the etiology of nsCL/P. To identify high impact protein-altering DNMs that contribute to the risk of nsCL/P, we conducted whole-genome sequencing (WGS) analyses in 130 African case-parent trios (affected probands and unaffected parents). We identified 162 high confidence protein-altering DNMs some of which are based on available evidence, contribute to the risk of nsCL/P. These include novel protein-truncating DNMs in the ACTL6A, ARHGAP10, MINK1, TMEM5 and TTN genes; as well as missense variants in ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TULP4. Many of these protein-altering DNMs were predicted to be pathogenic. Analysis using mouse transcriptomics data showed that some of these genes are expressed during the development of primary and secondary palate. Gene-set enrichment analysis of the protein-altering DNMs identified palatal development and neural crest migration among the few processes that were significantly enriched. These processes are directly involved in the etiopathogenesis of clefting. The analysis of the coding sequence in the WGS data provides more evidence of the opportunity for novel findings in the African genome.

Original languageEnglish
Article number11743
Number of pages14
JournalScientific Reports
Issue number1
Publication statusPublished - 11 Jul 2022


  • Animals
  • Brain/abnormalities
  • Cleft Lip/genetics
  • Cleft Palate/genetics
  • Genetic Predisposition to Disease
  • Genome-Wide Association Study
  • Mice
  • Mutation
  • Polymorphism, Single Nucleotide

ASJC Scopus subject areas

  • General


Dive into the research topics of 'Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate'. Together they form a unique fingerprint.

Cite this