Scientific Reports (Jul 2022)
Whole-genome sequencing reveals de-novo mutations associated with nonsyndromic cleft lip/palate
- Waheed Awotoye,
- 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 Oladayo,
- Sami 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
Affiliations
- Waheed Awotoye
- Iowa Institute for Oral Health Research, University of Iowa
- Peter A. Mossey
- Department of Orthodontics, University of Dundee
- Jacqueline B. Hetmanski
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health
- Lord J. J. Gowans
- Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology
- Mekonen A. Eshete
- Surgical Department, School Medicine, Addis Ababa University
- Wasiu L. Adeyemo
- Department of Oral and Maxillofacial Surgery, University of Lagos
- Azeez Alade
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Erliang Zeng
- Division of Biostatistics and Computational Biology, College of Dentistry, University of Iowa
- Olawale Adamson
- Department of Oral and Maxillofacial Surgery, University of Lagos
- Thirona Naicker
- Department of Pediatrics, University of KwaZulu-Natal
- Deepti Anand
- Department of Biological Sciences, University of Delaware
- Chinyere Adeleke
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Tamara Busch
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Mary Li
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Aline Petrin
- Iowa Institute for Oral Health Research, University of Iowa
- Babatunde S. Aregbesola
- Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University
- Ramat O. Braimah
- Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University
- Fadekemi O. Oginni
- Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University
- Ayodeji O. Oladele
- Department of Oral and Maxillofacial Surgery, Obafemi Awolowo University
- Abimbola Oladayo
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Sami Kayali
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Joy Olotu
- Department of Anatomy, University of Port Harcourt
- Mohaned Hassan
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- John Pape
- Department of Oral Pathology, Radiology and Medicine, College of Dentistry, University of Iowa
- Peter Donkor
- Department of Surgery, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology
- Fareed K. N. Arthur
- Department of Biochemistry and Biotechnology, Kwame Nkrumah University of Science and Technology
- Solomon Obiri-Yeboah
- Department of Maxillofacial Sciences, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology
- Daniel K. Sabbah
- Department of Child Oral Health and Orthodontics, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology
- Pius Agbenorku
- Department of Surgery, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology
- Gyikua Plange-Rhule
- Department of Child Health, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology
- Alexander Acheampong Oti
- Department of Maxillofacial Sciences, School of Medicine and Dentistry, Kwame Nkrumah University of Science and Technology
- Rose A. Gogal
- Center for Biocatalysis and Bioprocessing (CBB), University of Iowa
- Terri H. Beaty
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health
- Margaret Taub
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health
- Mary L. Marazita
- Center for Craniofacial and Dental Genetics, Department of Oral and Craniofacial Sciences, School of Dental Medicine, and Department of Human Genetics, Graduate School of Public Health, University of Pittsburgh
- Michael J. Schnieders
- Center for Biocatalysis and Bioprocessing (CBB), University of Iowa
- Salil A. Lachke
- Department of Biological Sciences, University of Delaware
- Adebowale A. Adeyemo
- National Human Genomic Research Institute
- Jeffrey C. Murray
- Department of Pediatrics, University of Iowa
- Azeez Butali
- Iowa Institute for Oral Health Research, University of Iowa
- DOI
- https://doi.org/10.1038/s41598-022-15885-1
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 1 – 14
Abstract
Abstract 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.