Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft 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; Olutayo James; Azeez Fashina; Modupe O. Ogunlewe; Thirona Naicker; Chinyere Adeleke; Tamara Busch; Mary Li; Aline Petrin; Abimbola Oladayo; Sami Kayali; Joy Olotu; Veronica Sule; Mohaned Hassan; John Pape; Emmanuel T. Aladenika; Peter Donkor; Fareed K. N. Arthur; Solomon Obiri-Yeboah; Daniel K. Sabbah; Pius Agbenorku; Debashree Ray; Gyikua Plange-Rhule; Alexander Acheampong Oti; Daniah Albokhari; Nara Sobreira; Martine Dunnwald; Terri H. Beaty; Margaret Taub; Mary L. Marazita; Adebowale A. Adeyemo; Jeffrey C. Murray; Azeez Butali

doi:10.1177/10556656221135926

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft 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
, Olutayo James
, Azeez Fashina
, Modupe O. Ogunlewe
, Thirona Naicker
, Chinyere Adeleke
, Tamara Busch
, Mary Li
, Aline Petrin
, Abimbola Oladayo
, Sami Kayali
, Joy Olotu

Veronica Sule, Mohaned Hassan, John Pape, Emmanuel T. Aladenika, Peter Donkor, Fareed K. N. Arthur, Solomon Obiri-Yeboah, Daniel K. Sabbah, Pius Agbenorku, Debashree Ray, Gyikua Plange-Rhule, Alexander Acheampong Oti, Daniah Albokhari, Nara Sobreira, Martine Dunnwald, Terri H. Beaty, Margaret Taub, Mary L. Marazita, Adebowale A. Adeyemo, Jeffrey C. Murray, Azeez Butali (Lead / Corresponding author)

Dentistry

Research output: Contribution to journal › Article › peer-review

4 Citations (Scopus)

422 Downloads (Pure)

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.

Original language	English
Pages (from-to)	697-705
Number of pages	9
Journal	Cleft Palate-Craniofacial Journal
Volume	61
Issue number	4
Early online date	16 Nov 2022
DOIs	https://doi.org/10.1177/10556656221135926
Publication status	Published - Apr 2024

Keywords

AFDN
cell adhesion molecule
cleft
craniofacial genetics
damaging mutations
next-generation sequencing
pathogenic variants
thermodynamics

ASJC Scopus subject areas

Oral Surgery
Otorhinolaryngology

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Cite this

Awotoye, W., Mossey, P. A., Hetmanski, J. B., Gowans, L. J. J., Eshete, M. A., Adeyemo, W. L., Alade, A., Zeng, E., Adamson, O., James, O., Fashina, A., Ogunlewe, M. O., Naicker, T., Adeleke, C., Busch, T., Li, M., Petrin, A., Oladayo, A., Kayali, S., ... Butali, A. (2024). Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate. Cleft Palate-Craniofacial Journal, 61(4), 697-705. https://doi.org/10.1177/10556656221135926

@article{7f01798abe174b458010bffaa693026b,

title = "Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate",

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.",

keywords = "AFDN, cell adhesion molecule, cleft, craniofacial genetics, damaging mutations, next-generation sequencing, pathogenic variants, thermodynamics",

author = "Waheed Awotoye and Mossey, \{Peter A.\} and Hetmanski, \{Jacqueline B.\} and Gowans, \{Lord J. J.\} and Eshete, \{Mekonen A.\} and Adeyemo, \{Wasiu L.\} and Azeez Alade and Erliang Zeng and Olawale Adamson and Olutayo James and Azeez Fashina and Ogunlewe, \{Modupe O.\} and Thirona Naicker and Chinyere Adeleke and Tamara Busch and Mary Li and Aline Petrin and Abimbola Oladayo and Sami Kayali and Joy Olotu and Veronica Sule and Mohaned Hassan and John Pape and Aladenika, \{Emmanuel T.\} and Peter Donkor and Arthur, \{Fareed K. N.\} and Solomon Obiri-Yeboah and Sabbah, \{Daniel K.\} and Pius Agbenorku and Debashree Ray and Gyikua Plange-Rhule and Oti, \{Alexander Acheampong\} and Daniah Albokhari and Nara Sobreira and Martine Dunnwald and Beaty, \{Terri H.\} and Margaret Taub and Marazita, \{Mary L.\} and Adeyemo, \{Adebowale A.\} and Murray, \{Jeffrey C.\} and Azeez Butali",

note = "Copyright: {\textcopyright} 2022, American Cleft Palate-Craniofacial Association.",

year = "2024",

month = apr,

doi = "10.1177/10556656221135926",

language = "English",

volume = "61",

pages = "697--705",

journal = "Cleft Palate-Craniofacial Journal",

issn = "1055-6656",

publisher = "SAGE Publications",

number = "4",

}

Awotoye, W, Mossey, PA, Hetmanski, JB, Gowans, LJJ, Eshete, MA, Adeyemo, WL, Alade, A, Zeng, E, Adamson, O, James, O, Fashina, A, Ogunlewe, MO, Naicker, T, Adeleke, C, Busch, T, Li, M, Petrin, A, Oladayo, A, Kayali, S, Olotu, J, Sule, V, Hassan, M, Pape, J, Aladenika, ET, Donkor, P, Arthur, FKN, Obiri-Yeboah, S, Sabbah, DK, Agbenorku, P, Ray, D, Plange-Rhule, G, Oti, AA, Albokhari, D, Sobreira, N, Dunnwald, M, Beaty, TH, Taub, M, Marazita, ML, Adeyemo, AA, Murray, JC & Butali, A 2024, 'Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate', Cleft Palate-Craniofacial Journal, vol. 61, no. 4, pp. 697-705. https://doi.org/10.1177/10556656221135926

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

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 - 697

EP - 705

JO - Cleft Palate-Craniofacial Journal

JF - Cleft Palate-Craniofacial Journal

IS - 4

ER -

Damaging Mutations in AFDN Contribute to Risk of Nonsyndromic Cleft Lip With or Without Cleft Palate

Abstract

Keywords

ASJC Scopus subject areas

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