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      Novel IRF6 mutations in Chinese Han families with Van der Woude syndrome

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          Abstract

          Background

          Interferon Regulatory Factor 6 ( IRF6) gene encodes a member of the IRF family of transcription factors. Mutations in IRF6 cause Van der Woude Syndrome (VWS), which is the most common malformation of syndromic orofacial clefts in humans.

          Methods

          Here, we performed sequencing studies of six families with VWS in the Chinese Han population. The entire IRF6‐coding region and the exon–intron boundaries including exons 3–8 and part of exon 9 were screened among all the collected family members by Sanger sequencing.

          Results

          We found a novel splice site variant c.175‐6T>A, two novel missense variants (p.Lys66Arg and p.Pro107Thr), in addition with a previously reported missense variant (p.Leu87Phe), which were all located in and nearby exon 4 of IRF6. Meanwhile, a novel frameshift variant p.G257Vfs*46 in exon 7 of IRF6 was also detected. All the mutations presented to be co‐segregated in each family.

          Conclusion

          Our study has advanced the understanding of the genetic architecture of VWS and provides the basis for genetic counseling, antenatal diagnosis, and gene therapy of high risk groups.

          Abstract

          It is a study on IRF6 sequencing of six Van der Woude Syndrome families in the Chinese Han population. And four novel variants were detected in the study.

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          Most cited references16

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          Mutations in IRF6 cause Van der Woude and popliteal pterygium syndromes.

          Interferon regulatory factor 6 (IRF6) belongs to a family of nine transcription factors that share a highly conserved helix-turn-helix DNA-binding domain and a less conserved protein-binding domain. Most IRFs regulate the expression of interferon-alpha and -beta after viral infection, but the function of IRF6 is unknown. The gene encoding IRF6 is located in the critical region for the Van der Woude syndrome (VWS; OMIM 119300) locus at chromosome 1q32-q41 (refs 2,3). The disorder is an autosomal dominant form of cleft lip and palate with lip pits, and is the most common syndromic form of cleft lip or palate. Popliteal pterygium syndrome (PPS; OMIM 119500) is a disorder with a similar orofacial phenotype that also includes skin and genital anomalies. Phenotypic overlap and linkage data suggest that these two disorders are allelic. We found a nonsense mutation in IRF6 in the affected twin of a pair of monozygotic twins who were discordant for VWS. Subsequently, we identified mutations in IRF6 in 45 additional unrelated families affected with VWS and distinct mutations in 13 families affected with PPS. Expression analyses showed high levels of Irf6 mRNA along the medial edge of the fusing palate, tooth buds, hair follicles, genitalia and skin. Our observations demonstrate that haploinsufficiency of IRF6 disrupts orofacial development and are consistent with dominant-negative mutations disturbing development of the skin and genitalia.
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            Dominant Mutations in GRHL3 Cause Van der Woude Syndrome and Disrupt Oral Periderm Development

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              Prevalence and nonrandom distribution of exonic mutations in interferon regulatory factor 6 in 307 families with Van der Woude syndrome and 37 families with popliteal pterygium syndrome.

              Interferon regulatory factor 6 encodes a member of the IRF family of transcription factors. Mutations in interferon regulatory factor 6 cause Van der Woude and popliteal pterygium syndrome, two related orofacial clefting disorders. Here, we compared and contrasted the frequency and distribution of exonic mutations in interferon regulatory factor 6 between two large geographically distinct collections of families with Van der Woude and between one collection of families with popliteal pterygium syndrome. We performed direct sequence analysis of interferon regulatory factor 6 exons on samples from three collections, two with Van der Woude and one with popliteal pterygium syndrome. We identified mutations in interferon regulatory factor 6 exons in 68% of families in both Van der Woude collections and in 97% of families with popliteal pterygium syndrome. In sum, 106 novel disease-causing variants were found. The distribution of mutations in the interferon regulatory factor 6 exons in each collection was not random; exons 3, 4, 7, and 9 accounted for 80%. In the Van der Woude collections, the mutations were evenly divided between protein truncation and missense, whereas most mutations identified in the popliteal pterygium syndrome collection were missense. Further, the missense mutations associated with popliteal pterygium syndrome were localized significantly to exon 4, at residues that are predicted to bind directly to DNA. The nonrandom distribution of mutations in the interferon regulatory factor 6 exons suggests a two-tier approach for efficient mutation screens for interferon regulatory factor 6. The type and distribution of mutations are consistent with the hypothesis that Van der Woude is caused by haploinsufficiency of interferon regulatory factor 6. On the other hand, the distribution of popliteal pterygium syndrome-associated mutations suggests a different, though not mutually exclusive, effect on interferon regulatory factor 6 function.
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                Author and article information

                Contributors
                hemiao@whu.edu.cn
                Journal
                Mol Genet Genomic Med
                Mol Genet Genomic Med
                10.1002/(ISSN)2324-9269
                MGG3
                Molecular Genetics & Genomic Medicine
                John Wiley and Sons Inc. (Hoboken )
                2324-9269
                28 February 2020
                May 2020
                : 8
                : 5 ( doiID: 10.1002/mgg3.v8.5 )
                : e1196
                Affiliations
                [ 1 ] State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) and Key Laboratory of Oral Biomedicine Ministry of Education School & Hospital of Stomatology Wuhan University Wuhan China
                [ 2 ] Key Laboratory of Analytical Chemistry for Biology and Medicine (Ministry of Education) College of Chemistry and Molecular Sciences State Key Laboratory of Virology, Wuhan University Wuhan China
                Author notes
                [*] [* ] Correspondence

                Miao He, State Key Laboratory Breeding Base of Basic Science of Stomatology (Hubei‐MOST) and Key Laboratory of Oral Biomedicine Ministry of Education, School & Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.

                Email: hemiao@ 123456whu.edu.cn

                Author information
                https://orcid.org/0000-0003-4817-5769
                https://orcid.org/0000-0001-8255-8072
                Article
                MGG31196
                10.1002/mgg3.1196
                7216816
                32108996
                99304fd4-cdbb-44ec-a77d-a7497b178fc7
                © 2020 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 14 January 2020
                : 02 February 2020
                : 14 February 2020
                Page count
                Figures: 3, Tables: 1, Pages: 9, Words: 4668
                Funding
                Funded by: Independent scientific research project of Wuhan University
                Award ID: 413000065
                Funded by: National Science Foundation of Hubei Province
                Award ID: 2018CFB507
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: 81970904
                Award ID: 81970923
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                May 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.8.1 mode:remove_FC converted:12.05.2020

                chinese han,interferon regulatory factor 6,sequencing study,van der woude syndrome

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