title: Compound heterozygosity of low-frequency promoter deletions and rare loss-of-function mutations in TXNL4A causes Burn-McKeown syndrome.
abstract: Mutations in components of the major spliceosome have been described in disorders with craniofacial anomalies, e.g., Nager syndrome and mandibulofacial dysostosis type Guion-Almeida. The U5 spliceosomal complex of eight highly conserved proteins is critical for pre-mRNA splicing. We identified biallelic mutations in TXNL4A, a member of this complex, in individuals with Burn-McKeown syndrome (BMKS). This rare condition is characterized by bilateral choanal atresia, hearing loss, cleft lip and/or palate, and other craniofacial dysmorphisms. Mutations were found in 9 of 11 affected families. In 8 families, affected individuals carried a rare loss-of-function mutation (nonsense, frameshift, or microdeletion) on one allele and a low-frequency 34 bp deletion (allele frequency 0.76%) in the core promoter region on the other allele. In a single highly consanguineous family, formerly diagnosed as oculo-oto-facial dysplasia, the four affected individuals were homozygous for a 34 bp promoter deletion, which differed from the promoter deletion in the other families. Reporter gene and in vivo assays showed that the promoter deletions led to reduced expression of TXNL4A. Depletion of TXNL4A (Dib1) in yeast demonstrated reduced assembly of the tri-snRNP complex. Our results indicate that BMKS is an autosomal-recessive condition, which is frequently caused by compound heterozygosity of low-frequency promoter deletions in combination with very rare loss-of-function mutations.
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany. Electronic address: dagmar.wieczorek@uni-due.de.
authors.forename: Dagmar
authors.initials: D
authors.lastname: Wieczorek
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: William G
authors.initials: WG
authors.lastname: Newman
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Thomas
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authors.lastname: Wieland
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Tea
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authors.lastname: Berulava
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Department of Neurology and Clinical Neurophysiology, Center for Parkinson's Disease and Movement Disorders, Schön Klinik München Schwabing, 80804 Munich, Germany.
authors.forename: Maria
authors.initials: M
authors.lastname: Kaffe
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Daniela
authors.initials: D
authors.lastname: Falkenstein
authors.affiliation: Institute for Clinical Chemistry and Laboratory Diagnostics, University Hospital Jena, 07747 Jena, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Beetz
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Elisabeth
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authors.lastname: Graf
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
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authors.lastname: Schwarzmayr
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Sofia
authors.initials: S
authors.lastname: Douzgou
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Jill
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authors.lastname: Clayton-Smith
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Daly
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Simon G
authors.initials: SG
authors.lastname: Williams
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Sanjeev S
authors.initials: SS
authors.lastname: Bhaskar
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Jill E
authors.initials: JE
authors.lastname: Urquhart
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: Beverley
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authors.lastname: Anderson
authors.affiliation: Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust as part of the Manchester Academic Health Science Centre, Manchester M13 9WL, UK.
authors.forename: James
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authors.lastname: O'Sullivan
authors.affiliation: Centre de Génétique, Centre Hospitalier Universitaire de Lille, Lille 59037, France.
authors.forename: Odile
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authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany.
authors.forename: Jasmin
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authors.lastname: Gundlach
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Johanna Christina
authors.initials: JC
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authors.affiliation: Department of Genetics, University Medical Center Groningen, University of Groningen, 9700 Groningen, the Netherlands.
authors.forename: Anthonie J
authors.initials: AJ
authors.lastname: van Essen
authors.affiliation: Department of Medical Genetics, Dr. Behcet Uz Children's Hospital, Izmir 35210, Turkey.
authors.forename: Filiz
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authors.lastname: Hazan
authors.affiliation: Craniofacial Center, Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Sarah
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authors.lastname: Park
authors.affiliation: Seattle Children's Hospital, Seattle, WA 98105, USA.
authors.forename: Anne
authors.initials: A
authors.lastname: Hing
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Alma
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authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Dietmar R
authors.initials: DR
authors.lastname: Lohmann
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Kerstin U
authors.initials: KU
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authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany.
authors.forename: Elisabeth
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authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Laura
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authors.lastname: Steenpaß
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Michael
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authors.affiliation: Institut für Humangenetik, Universitätsklinikum Leipzig, 04103 Leipzig, Germany; Universitätsklinik für Kinderheilkunde, Abteilung Humangenetik, Inselspital Bern, Bern 3010, Switzerland.
authors.forename: Johannes R
authors.initials: JR
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authors.affiliation: Neurogenetics Unit, Clinics Hospital of Ribeirao Preto, University of Sao Paulo, Sao Paulo 14048900, Brazil.
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authors.initials: CM
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authors.affiliation: Center for and Department of Human Genetics, University of Regensburg, 93053 Regensburg, Germany.
authors.forename: Ute
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authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany; Institut für Praenatale Medizin & Humangenetik, 42103 Wuppertal, Germany.
authors.forename: Eva-Christina
authors.initials: EC
authors.lastname: Prott
authors.affiliation: Research Unit of Molecular Epidemiology and Institute of Epidemiology II, Helmholtz Zentrum München 85764 Neuherberg, Germany.
authors.forename: Melanie
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authors.lastname: Waldenberger
authors.affiliation: Institute of Human Genetics, University of Bonn, 53127 Bonn, Germany; Department of Genomics, Life and Brain Center, University of Bonn, 53127 Bonn, Germany.
authors.forename: Anne C
authors.initials: AC
authors.lastname: Böhmer
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
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authors.lastname: Horsthemke
authors.affiliation: Faculty of Life Sciences, The University of Manchester, Michael Smith Building, Oxford Road, Manchester M13 9PT, UK.
authors.forename: Raymond T
authors.initials: RT
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authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institute of Human Genetics, Technische Universität München, 81675 Munich, Germany.
authors.forename: Thomas
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authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: John
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authors.lastname: Burn
authors.affiliation: Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
authors.forename: Hermann-Josef
authors.initials: HJ
authors.lastname: Lüdecke
authors.affiliation: Institute of Human Genetics, Helmholtz Zentrum München, 85764 Neuherberg, Germany; Institut für Praenatale Medizin & Humangenetik, 42103 Wuppertal, Germany.
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mesh_terms: D000483:Alleles; D002675:Child, Preschool; D002754:Choanal Atresia / Q000175:diagnosis / Q000235:genetics*; D003638:Deafness / Q000151:congenital* / Q000175:diagnosis / Q000235:genetics; D055354:Exosomes / Q000235:genetics; D019066:Facies; D005260:Female; D017353:Gene Deletion; D020869:Gene Expression Profiling; D005787:Gene Frequency; D017930:Genes, Reporter; D006330:Heart Defects, Congenital / Q000175:diagnosis / Q000235:genetics*; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D020411:Oligonucleotide Array Sequence Analysis; D010375:Pedigree; D010641:Phenotype; D011401:Promoter Regions, Genetic / Q000235:genetics*; D017415:Ribonucleoprotein, U5 Small Nuclear / Q000235:genetics* / Q000378:metabolism; D017422:Sequence Analysis, DNA; D017381:Spliceosomes / Q000235:genetics* / Q000378:metabolism
chemical_list: D017415:Ribonucleoprotein, U5 Small Nuclear; C506012:TXNL4A protein, human