TY - JOUR
T1 - Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate
AU - Awotoye, Waheed
AU - Mossey, Peter A.
AU - Hetmanski, Jacqueline B.
AU - Gowans, Lord J. J.
AU - Eshete, Mekonen A.
AU - Adeyemo, Wasiu L.
AU - Alade, Azeez
AU - Zeng, Erliang
AU - Adamson, Olawale
AU - James, Olutayo
AU - Fashina, Azeez
AU - Ogunlewe, Modupe O.
AU - Naicker, Thirona
AU - Adeleke, Chinyere
AU - Busch, Tamara
AU - Li, Mary
AU - Petrin, Aline
AU - Oladayo, Abimbola
AU - Kayali, Sami
AU - Olotu, Joy
AU - Sule, Veronica
AU - Hassan, Mohaned
AU - Pape, John
AU - Aladenika, Emmanuel T.
AU - Donkor, Peter
AU - Arthur, Fareed K. N.
AU - Obiri-Yeboah, Solomon
AU - Sabbah, Daniel K.
AU - Agbenorku, Pius
AU - Ray, Debashree
AU - Plange-Rhule, Gyikua
AU - Oti, Alexander Acheampong
AU - Albokhari, Daniah
AU - Sobreira, Nara
AU - Dunnwald, Martine
AU - Beaty, Terri H.
AU - Taub, Margaret
AU - Marazita, Mary L.
AU - Adeyemo, Adebowale A.
AU - Murray, Jeffrey C.
AU - Butali, Azeez
N1 - Copyright:
© 2022, American Cleft Palate-Craniofacial Association.
PY - 2024/4
Y1 - 2024/4
N2 - 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.
AB - 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.
KW - AFDN
KW - cell adhesion molecule
KW - cleft
KW - craniofacial genetics
KW - damaging mutations
KW - next-generation sequencing
KW - pathogenic variants
KW - thermodynamics
U2 - 10.1177/10556656221135926
DO - 10.1177/10556656221135926
M3 - Article
C2 - 36384317
SN - 1055-6656
VL - 61
SP - 545
EP - 554
JO - Cleft Palate-Craniofacial Journal
JF - Cleft Palate-Craniofacial Journal
IS - 4
ER -