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- Title
Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate.
- Authors
Awotoye, Waheed; Mossey, Peter A; Hetmanski, Jacqueline B; Gowans, Lord J J; Eshete, Mekonen A; Adeyemo, Wasiu L; Alade, Azeez; Zeng, Erliang; Adamson, Olawale; James, Olutayo; Fashina, Azeez; Ogunlewe, Modupe O; Naicker, Thirona; Adeleke, Chinyere; Busch, Tamara; Li, Mary; Petrin, Aline; Oladayo, Abimbola; Kayali, Sami; Olotu, Joy
- Abstract
Objectives : 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. Materials and Methods: 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. Results : 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. Conclusion : 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.
- Subjects
CLEFT lip -- Risk factors; RISK assessment; PROTEINS; COMPUTER simulation; CELL adhesion molecules; GENETIC polymorphisms; GENES; MOLECULAR structure; GENETIC mutation; CLEFT palate; SEQUENCE analysis; GENOMES; DISEASE risk factors
- Publication
Cleft Palate Craniofacial Journal, 2024, Vol 61, Issue 4, p697
- ISSN
1055-6656
- Publication type
Article
- DOI
10.1177/10556656221135926