FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate

Lina M. Moreno, Maria Adela Mansilla, Steve A. Bullard, Margaret E. Cooper, Tamara D. Busch, Junichiro Machida, Marla K. Johnson, David Brauer, Katherine Krahn, Sandy Daack-Hirsch, Jamie L'Heureux, Consuelo Valencia-Ramirez, Dora Rivera, Ana Maria López, Manuel A. Moreno, Anne Hing, Edward J. Lammer, Marilyn Jones, Kaare Christensen, Rolv T. Lie & 9 others Astanand Jugessur, Allen J. Wilcox, Peter Chines, Elizabeth Pugh, Kimberly Doheny, Mauricio Arcos-Burgos, Mary L. Marazita, Jeffrey C. Murray, Andrew C. Lidral

Research output: Contribution to journalArticle

Abstract

Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.

Original languageEnglish (US)
Pages (from-to)4879-4896
Number of pages18
JournalHuman molecular genetics
Volume18
Issue number24
DOIs
StatePublished - Nov 26 2009

Fingerprint

Cleft Lip
Cleft Palate
Single Nucleotide Polymorphism
Genes
Philippines
Colombia
Linkage Disequilibrium
Genetic Counseling
Missense Mutation
Nose
Haplotypes
Epithelium
Genome
Phenotype
Amino Acids
Mutation
Population

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

Cite this

Moreno, L. M., Mansilla, M. A., Bullard, S. A., Cooper, M. E., Busch, T. D., Machida, J., ... Lidral, A. C. (2009). FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Human molecular genetics, 18(24), 4879-4896. https://doi.org/10.1093/hmg/ddp444

FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. / Moreno, Lina M.; Mansilla, Maria Adela; Bullard, Steve A.; Cooper, Margaret E.; Busch, Tamara D.; Machida, Junichiro; Johnson, Marla K.; Brauer, David; Krahn, Katherine; Daack-Hirsch, Sandy; L'Heureux, Jamie; Valencia-Ramirez, Consuelo; Rivera, Dora; López, Ana Maria; Moreno, Manuel A.; Hing, Anne; Lammer, Edward J.; Jones, Marilyn; Christensen, Kaare; Lie, Rolv T.; Jugessur, Astanand; Wilcox, Allen J.; Chines, Peter; Pugh, Elizabeth; Doheny, Kimberly; Arcos-Burgos, Mauricio; Marazita, Mary L.; Murray, Jeffrey C.; Lidral, Andrew C.

In: Human molecular genetics, Vol. 18, No. 24, 26.11.2009, p. 4879-4896.

Research output: Contribution to journalArticle

Moreno, LM, Mansilla, MA, Bullard, SA, Cooper, ME, Busch, TD, Machida, J, Johnson, MK, Brauer, D, Krahn, K, Daack-Hirsch, S, L'Heureux, J, Valencia-Ramirez, C, Rivera, D, López, AM, Moreno, MA, Hing, A, Lammer, EJ, Jones, M, Christensen, K, Lie, RT, Jugessur, A, Wilcox, AJ, Chines, P, Pugh, E, Doheny, K, Arcos-Burgos, M, Marazita, ML, Murray, JC & Lidral, AC 2009, 'FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate', Human molecular genetics, vol. 18, no. 24, pp. 4879-4896. https://doi.org/10.1093/hmg/ddp444
Moreno LM, Mansilla MA, Bullard SA, Cooper ME, Busch TD, Machida J et al. FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. Human molecular genetics. 2009 Nov 26;18(24):4879-4896. https://doi.org/10.1093/hmg/ddp444
Moreno, Lina M. ; Mansilla, Maria Adela ; Bullard, Steve A. ; Cooper, Margaret E. ; Busch, Tamara D. ; Machida, Junichiro ; Johnson, Marla K. ; Brauer, David ; Krahn, Katherine ; Daack-Hirsch, Sandy ; L'Heureux, Jamie ; Valencia-Ramirez, Consuelo ; Rivera, Dora ; López, Ana Maria ; Moreno, Manuel A. ; Hing, Anne ; Lammer, Edward J. ; Jones, Marilyn ; Christensen, Kaare ; Lie, Rolv T. ; Jugessur, Astanand ; Wilcox, Allen J. ; Chines, Peter ; Pugh, Elizabeth ; Doheny, Kimberly ; Arcos-Burgos, Mauricio ; Marazita, Mary L. ; Murray, Jeffrey C. ; Lidral, Andrew C. / FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate. In: Human molecular genetics. 2009 ; Vol. 18, No. 24. pp. 4879-4896.
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abstract = "Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.",
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T1 - FOXE1 association with both isolated cleft lip with or without cleft palate, and isolated cleft palate

AU - Moreno, Lina M.

AU - Mansilla, Maria Adela

AU - Bullard, Steve A.

AU - Cooper, Margaret E.

AU - Busch, Tamara D.

AU - Machida, Junichiro

AU - Johnson, Marla K.

AU - Brauer, David

AU - Krahn, Katherine

AU - Daack-Hirsch, Sandy

AU - L'Heureux, Jamie

AU - Valencia-Ramirez, Consuelo

AU - Rivera, Dora

AU - López, Ana Maria

AU - Moreno, Manuel A.

AU - Hing, Anne

AU - Lammer, Edward J.

AU - Jones, Marilyn

AU - Christensen, Kaare

AU - Lie, Rolv T.

AU - Jugessur, Astanand

AU - Wilcox, Allen J.

AU - Chines, Peter

AU - Pugh, Elizabeth

AU - Doheny, Kimberly

AU - Arcos-Burgos, Mauricio

AU - Marazita, Mary L.

AU - Murray, Jeffrey C.

AU - Lidral, Andrew C.

PY - 2009/11/26

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N2 - Nonsyndromic orofacial clefts are a common complex birth defect caused by genetic and environmental factors and/or their interactions. A previous genome-wide linkage scan discovered a novel locus for cleft lip with or without cleft palate (CL/P) at 9q22-q33. To identify the etiologic gene, we undertook an iterative and complementary fine mapping strategy using family-based CL/P samples from Colombia, USA and the Philippines. Candidate genes within 9q22-q33 were sequenced, revealing 32 new variants. Concurrently, 397 SNPs spanning the 9q22-q33 2-LOD-unit interval were tested for association. Significant SNP and haplotype association signals (P = 1.45E - 08) narrowed the interval to a 200 kb region containing: FOXE1, C9ORF156 and HEMGN. Association results were replicated in CL/P families of European descent and when all populations were combined the two most associated SNPs, rs3758249 (P = 5.01E - 13) and rs4460498 (P = 6.51E - 12), were located inside a 70 kb high linkage disequilibrium block containing FOXE1. Association signals for Caucasians and Asians clustered 5′ and 3′ of FOXE1, respectively. Isolated cleft palate (CP) was also associated, indicating that FOXE1 plays a role in two phenotypes thought to be genetically distinct. Foxe1 expression was found in the epithelium undergoing fusion between the medial nasal and maxillary processes. Mutation screens of FOXE1 identified two family-specific missense mutations at highly conserved amino acids. These data indicate that FOXE1 is a major gene for CL/P and provides new insights for improved counseling and genetic interaction studies.

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