Journal article
Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate
The Cleft palate-craniofacial journal, Vol.61(4), pp.697-705
04/2024
DOI: 10.1177/10556656221135926
PMCID: PMC10185709
PMID: 36384317
Abstract
Novel or rare damaging mutations have been implicated in the developmental pathogenesis of nonsyndromic cleft lip with or without cleft palate (nsCL ± P). Thus, we investigated the human genome for high-impact mutations that could explain the risk of nsCL ± P in our cohorts. We conducted next-generation sequencing (NGS) analysis of 130 nsCL ± P case-parent African trios to identify pathogenic variants that contribute to the risk of clefting. We replicated this analysis using whole-exome sequence data from a Brazilian nsCL ± P cohort. Computational analyses were then used to predict the mechanism by which these variants could result in increased risks for nsCL ± P. We discovered damaging mutations within the AFDN gene, a cell adhesion molecule (CAMs) that was previously shown to contribute to cleft palate in mice. These mutations include p.Met1164Ile, p.Thr453Asn, p.Pro1638Ala, p.Arg669Gln, p.Ala1717Val, and p.Arg1596His. We also discovered a novel splicing p.Leu1588Leu mutation in this protein. Computational analysis suggests that these amino acid changes affect the interactions with other cleft-associated genes including nectins (PVRL1, PVRL2, PVRL3, and PVRL4) CDH1, CTNNA1, and CTNND1. This is the first report on the contribution of AFDN to the risk for nsCL ± P in humans. AFDN encodes AFADIN, an important CAM that forms calcium-independent complexes with nectins 1 and 4 (encoded by the genes PVRL1 and PVRL4). This discovery shows the power of NGS analysis of multiethnic cleft samples in combination with a computational approach in the understanding of the pathogenesis of nsCL ± P.
Details
- Title: Subtitle
- Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate
- Creators
- Waheed Awotoye - University of IowaPeter A Mossey - University of DundeeJacqueline B Hetmanski - Johns Hopkins UniversityLord J J Gowans - Kwame Nkrumah University of Science and TechnologyMekonen A Eshete - Addis Ababa UniversityWasiu L Adeyemo - University of LagosAzeez Alade - University of IowaErliang Zeng - University of IowaOlawale Adamson - University of LagosOlutayo James - University of LagosAzeez Fashina - University of LagosModupe O Ogunlewe - University of LagosThirona Naicker - University of KwaZulu-NatalChinyere Adeleke - University of IowaTamara Busch - University of IowaMary Li - University of IowaAline Petrin - University of IowaAbimbola Oladayo - University of IowaSami Kayali - University of IowaJoy Olotu - University of Port HarcourtVeronica Sule - University of IowaMohaned Hassan - University of IowaJohn Pape - University of IowaEmmanuel T Aladenika - University of IowaPeter Donkor - Kwame Nkrumah University of Science and TechnologyFareed K N Arthur - Kwame Nkrumah University of Science and TechnologySolomon Obiri-Yeboah - Kwame Nkrumah University of Science and TechnologyDaniel K Sabbah - Kwame Nkrumah University of Science and TechnologyPius Agbenorku - Kwame Nkrumah University of Science and TechnologyDebashree Ray - BloombergGyikua Plange-Rhule - Kwame Nkrumah University of Science and TechnologyAlexander Acheampong Oti - Kwame Nkrumah University of Science and TechnologyDaniah Albokhari - McKusick-Nathans Institute of Genetic Medicine, 1466Johns Hopkins University, Baltimore, MD, USA.Nara Sobreira - University of BaltimoreMartine Dunnwald - University of IowaTerri H Beaty - Johns Hopkins UniversityMargaret Taub - Johns Hopkins UniversityMary L Marazita - University of PittsburghAdebowale A Adeyemo - National Human Genome Research InstituteJeffrey C Murray - University of IowaAzeez Butali - University of Iowa
- Resource Type
- Journal article
- Publication Details
- The Cleft palate-craniofacial journal, Vol.61(4), pp.697-705
- DOI
- 10.1177/10556656221135926
- PMID
- 36384317
- PMCID
- PMC10185709
- NLM abbreviation
- Cleft Palate Craniofac J
- ISSN
- 1055-6656
- eISSN
- 1545-1569
- Grant note
- DOI: 10.13039/100000072, name: National Institute of Dental and Craniofacial Research, award: DE28300
- Language
- English
- Electronic publication date
- 11/16/2022
- Date published
- 04/2024
- Academic Unit
- Preventive and Community Dentistry; Roy J. Carver Department of Biomedical Engineering; Orthodontics; Oral Pathology, Radiology and Medicine; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Iowa Neuroscience Institute; Biostatistics; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
- Record Identifier
- 9984318358802771
Metrics
64 Record Views