Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate

Theresa M. Zucchero, Margaret E. Cooper, Brion Maher, Sandra Daack-Hirsch, Buena Nepomuceno, Lucilene Ribeiro, Diana Caprau, Kaare Christensen, Yasushi Suzuki, Junichiro Machida, Nagato Natsume, Koh Ichiro Yoshiura, Alexandre R. Vieira, Ieda M. Orioli, Eduardo E. Castilla, Lina Moreno, Mauricio Arcos-Burgos, Andrew C. Lidral, L. Leigh Field, You E. Liu & 9 others Ajit Ray, Toby H. Goldstein, Rebecca E. Schultz, Min Shi, Marla K. Johnson, Shinji Kondo, Brian C. Schutte, Mary L. Marazita, Jeffrey C. Murray

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P-9); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

Original languageEnglish (US)
Pages (from-to)769-780
Number of pages12
JournalNew England Journal of Medicine
Volume351
Issue number8
DOIs
StatePublished - Aug 19 2004
Externally publishedYes

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Interferon Regulatory Factors
Cleft Lip
Cleft Palate
Genes
South America
Valine
Population
Isoleucine
Genetic Counseling
Haplotypes
Single Nucleotide Polymorphism
Alleles
Amino Acids
Recurrence

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Zucchero, T. M., Cooper, M. E., Maher, B., Daack-Hirsch, S., Nepomuceno, B., Ribeiro, L., ... Murray, J. C. (2004). Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. New England Journal of Medicine, 351(8), 769-780. https://doi.org/10.1056/NEJMoa032909

Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. / Zucchero, Theresa M.; Cooper, Margaret E.; Maher, Brion; Daack-Hirsch, Sandra; Nepomuceno, Buena; Ribeiro, Lucilene; Caprau, Diana; Christensen, Kaare; Suzuki, Yasushi; Machida, Junichiro; Natsume, Nagato; Yoshiura, Koh Ichiro; Vieira, Alexandre R.; Orioli, Ieda M.; Castilla, Eduardo E.; Moreno, Lina; Arcos-Burgos, Mauricio; Lidral, Andrew C.; Field, L. Leigh; Liu, You E.; Ray, Ajit; Goldstein, Toby H.; Schultz, Rebecca E.; Shi, Min; Johnson, Marla K.; Kondo, Shinji; Schutte, Brian C.; Marazita, Mary L.; Murray, Jeffrey C.

In: New England Journal of Medicine, Vol. 351, No. 8, 19.08.2004, p. 769-780.

Research output: Contribution to journalArticle

Zucchero, TM, Cooper, ME, Maher, B, Daack-Hirsch, S, Nepomuceno, B, Ribeiro, L, Caprau, D, Christensen, K, Suzuki, Y, Machida, J, Natsume, N, Yoshiura, KI, Vieira, AR, Orioli, IM, Castilla, EE, Moreno, L, Arcos-Burgos, M, Lidral, AC, Field, LL, Liu, YE, Ray, A, Goldstein, TH, Schultz, RE, Shi, M, Johnson, MK, Kondo, S, Schutte, BC, Marazita, ML & Murray, JC 2004, 'Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate', New England Journal of Medicine, vol. 351, no. 8, pp. 769-780. https://doi.org/10.1056/NEJMoa032909
Zucchero, Theresa M. ; Cooper, Margaret E. ; Maher, Brion ; Daack-Hirsch, Sandra ; Nepomuceno, Buena ; Ribeiro, Lucilene ; Caprau, Diana ; Christensen, Kaare ; Suzuki, Yasushi ; Machida, Junichiro ; Natsume, Nagato ; Yoshiura, Koh Ichiro ; Vieira, Alexandre R. ; Orioli, Ieda M. ; Castilla, Eduardo E. ; Moreno, Lina ; Arcos-Burgos, Mauricio ; Lidral, Andrew C. ; Field, L. Leigh ; Liu, You E. ; Ray, Ajit ; Goldstein, Toby H. ; Schultz, Rebecca E. ; Shi, Min ; Johnson, Marla K. ; Kondo, Shinji ; Schutte, Brian C. ; Marazita, Mary L. ; Murray, Jeffrey C. / Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate. In: New England Journal of Medicine. 2004 ; Vol. 351, No. 8. pp. 769-780.
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abstract = "BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P-9); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.",
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T1 - Interferon regulatory factor 6 (IRF6) gene variants and the risk of isolated cleft lip or palate

AU - Zucchero, Theresa M.

AU - Cooper, Margaret E.

AU - Maher, Brion

AU - Daack-Hirsch, Sandra

AU - Nepomuceno, Buena

AU - Ribeiro, Lucilene

AU - Caprau, Diana

AU - Christensen, Kaare

AU - Suzuki, Yasushi

AU - Machida, Junichiro

AU - Natsume, Nagato

AU - Yoshiura, Koh Ichiro

AU - Vieira, Alexandre R.

AU - Orioli, Ieda M.

AU - Castilla, Eduardo E.

AU - Moreno, Lina

AU - Arcos-Burgos, Mauricio

AU - Lidral, Andrew C.

AU - Field, L. Leigh

AU - Liu, You E.

AU - Ray, Ajit

AU - Goldstein, Toby H.

AU - Schultz, Rebecca E.

AU - Shi, Min

AU - Johnson, Marla K.

AU - Kondo, Shinji

AU - Schutte, Brian C.

AU - Marazita, Mary L.

AU - Murray, Jeffrey C.

PY - 2004/8/19

Y1 - 2004/8/19

N2 - BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P-9); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

AB - BACKGROUND: Cleft lip or palate (or the two in combination) is a common birth defect that results from a mixture of genetic and environmental factors. We searched for a specific genetic factor contributing to this complex trait by examining large numbers of affected patients and families and evaluating a specific candidate gene. METHODS: We identified the gene that encodes interferon regulatory factor 6 (IRF6) as a candidate gene on the basis of its involvement in an autosomal dominant form of cleft lip and palate, Van der Woude's syndrome. A single-nucleotide polymorphism in this gene results in either a valine or an isoleucine at amino acid position 274 (V274I). We carried out transmission-disequilibrium testing for V274I in 8003 individual subjects in 1968 families derived from 10 populations with ancestry in Asia, Europe, and South America, haplotype and linkage analyses, and case-control analyses, and determined the risk of cleft lip or palate that is associated with genetic variation in IRF6. RESULTS: Strong evidence of overtransmission of the valine (V) allele was found in the entire population data set (P-9); moreover, the results for some individual populations from South America and Asia were highly significant. Variation at IRF6 was responsible for 12 percent of the genetic contribution to cleft lip or palate and tripled the risk of recurrence in families that had already had one affected child. CONCLUSIONS: DNA-sequence variants associated with IRF6 are major contributors to cleft lip, with or without cleft palate. The contribution of variants in single genes to cleft lip or palate is an important consideration in genetic counseling.

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