Whole-genome Sequencing Reveals De-novo Mutations Associated with Nonsyndromic Cleft Lip/Palate
Author:
Awotoye Waheed1, Mossey Peter A.2, Hetmanski Jacqueline B.3, Gowans Lord Jephthah Joojo4, Eshete Mekonen A.5, Adeyemo Wasiu L.6, Alade Azeez1, Zeng Erliang1, Adamson Olawale6, Naicker Thirona7, Anand Deepti8, Adeleke Chinyere1, Busch Tamara1, Li Mary1, Petrin Aline1, Aregbesola Babatunde S.9, Braimah Ramat O.9, Oginni Fadekemi O.9, Oladele Ayodeji O.9, Oladayo Abimbola1, Kayali Sami1, Olotu Joy10, Hassan Mohaned1, Pape John1, Donkor Peter4, Arthur Fareed K.N.4, Obiri-Yeboah Solomon4, Sabbah Daniel K.4, Agbenorku Pius4, Plange-Rhule Gyikua4, Oti Alexander Acheampong4, Gogal Rose A.1, Beaty Terri H.3, Taub Margaret3, Marazita Mary L.11, Schnieders Michael J.1, Lachke Salil A.8, Adeyemo Adebowale A.12, Murray Jeffrey C.1, Butali Azeez1
Affiliation:
1. University of Iowa 2. University of Dundee 3. Johns Hopkins Bloomberg School of Public Health 4. Kwame Nkrumah University of Science and Technology 5. Addis Ababa University 6. University of Lagos 7. University of KwaZulu-Natal 8. University of Delaware 9. Obafemi Awolowo University 10. University of Port Harcourt 11. University of Pittsburgh 12. National Human Genomic Research Institute
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 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 that contribute to the risk of nsCL/P. These include novel loss-of-function 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. Experimental evidence showed that ACAN, DHRS3, DLX6, EPHB2, FKBP10, KMT2D, MINK1, RECQL4, SEMA3C, SEMA4D, SHH, TP63, and TTN genes contribute to facial development and mutations in these genes could contribute to CL/P. Association studies have identified TULP4 as a potential cleft candidate gene, while ARHGAP10 interacts with CTNNB1 to control WNT signaling. DLX6, EPHB2, SEMA3C and SEMA4D harbor novel damaging DNMs that may affect their role in neural crest migration and palatal development. This discovery of pathogenic DNMs also confirms the power of WGS analysis of trios in the discovery of potential pathogenic variants.
Publisher
Research Square Platform LLC
Cited by
2 articles.
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