title: Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes.
abstract: Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Department of Pediatrics, Walter Reed National Military Medical Center, Bethesda, MD 20892, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Marchegiani
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Taylor
authors.initials: T
authors.lastname: Davis
authors.affiliation: Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors.forename: Federico
authors.initials: F
authors.lastname: Tessadori
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.affiliation: Department of Medical, Oral, and Biotechnological Sciences, University of G. d' Annunzio Chieti and Pescara, Chieti 66100, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Brancati
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Haigen
authors.initials: H
authors.lastname: Huang
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Elise
authors.initials: E
authors.lastname: Valkanas
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pusey
authors.affiliation: Medizinische Fakultät und Universitätsklinikum Magdeburg, Institute of Human Genetics, 39120 Magdeburg, Germany.
authors.forename: Denny
authors.initials: D
authors.lastname: Schanze
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Hanka
authors.initials: H
authors.lastname: Venselaar
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Anneke T
authors.initials: AT
authors.lastname: Vulto-van Silfhout
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute/NIH, Bethesda, MD 20892, USA.
authors.forename: Lynne A
authors.initials: LA
authors.lastname: Wolfe
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute/NIH, Bethesda, MD 20892, USA.
authors.forename: Cynthia J
authors.initials: CJ
authors.lastname: Tifft
authors.affiliation: Office of Research Services, Division of Veterinary Resources, NIH, Bethesda, MD 20892, USA.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: Zerfas
authors.affiliation: Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome 00167, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Zambruno
authors.affiliation: Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
authors.forename: Ariana
authors.initials: A
authors.lastname: Kariminejad
authors.affiliation: Kerman University of Medical Sciences, Kerman 76175, Iran.
authors.forename: Farahnaz
authors.initials: F
authors.lastname: Sabbagh-Kermani
authors.affiliation: National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
authors.forename: Janice
authors.initials: J
authors.lastname: Lee
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Maria G
authors.initials: MG
authors.lastname: Tsokos
authors.affiliation: Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Chyi-Chia R
authors.initials: CC
authors.lastname: Lee
authors.affiliation: Departamento de Genetica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Sao Paulo 14049, Brazil.
authors.forename: Victor
authors.initials: V
authors.lastname: Ferraz
authors.affiliation: Departamento de Genetica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Sao Paulo 14049, Brazil.
authors.forename: Eduarda Morgana
authors.initials: EM
authors.lastname: da Silva
authors.affiliation: Department of Medical Genetics, T.C. Thompson Children's Hospital, Chattanooga, TN 37403, USA.
authors.forename: Cathy A
authors.initials: CA
authors.lastname: Stevens
authors.affiliation: Department of Plastic and Reconstructive Surgery, University Hospital of Ghent, Ghent 9000, Belgium.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Roche
authors.affiliation: Institute of Human Genetics, Johannes Gutenberg University, Mainz 55131, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.affiliation: Clinical Genetics Unit, Birmingham Women's Healthcare Trust, Birmingham B15 2TG, UK.
authors.forename: Peter
authors.initials: P
authors.lastname: Farndon
authors.affiliation: ECEMC (Spanish Collaborative Study of Congenital Malformations), CIAC, Instituto de Investigación de Enfermedades Raras (IIER), Instituto de Salud Carlos III; and CIBER de Enfermedades Raras (CIBERER)-U724, Madrid 28029, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Bermejo-Sanchez
authors.affiliation: Unit on Pediatric, Developmental, and Genetic Eye Disease, National Eye Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Brian P
authors.initials: BP
authors.lastname: Brooks
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Valerie
authors.initials: V
authors.lastname: Maduro
authors.affiliation: Department of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy.
authors.forename: Bruno
authors.initials: B
authors.lastname: Dallapiccola
authors.affiliation: Unidad de Genética Médica, Servicio de Pediatría, GCV-CIBERER Hospital Clínico Universitario "Lozano Blesa," Facultad de Medicina, Universidad de Zaragoza, 50009 Zaragoza, Spain.
authors.forename: Feliciano J
authors.initials: FJ
authors.lastname: Ramos
authors.affiliation: Department of Paediatrics and Adolescent Medicine, Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Hon-Yin Brian
authors.initials: HY
authors.lastname: Chung
authors.affiliation: Service de genetique medicale, CHU Nantes, 44093 Nantes, France and Inserm, UMR957, Faculté de Médecine, 44093 Nantes, France.
authors.forename: Cédric
authors.initials: C
authors.lastname: Le Caignec
authors.affiliation: Special Care Dentistry Center, Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo 05508-070, Brazil.
authors.forename: Fabiana
authors.initials: F
authors.lastname: Martins
authors.affiliation: Department of Dermatology, University of Pretoria, Pretoria 0028, Republic of South Africa.
authors.forename: Witold K
authors.initials: WK
authors.lastname: Jacyk
authors.affiliation: Department of Pediatrics, S. Orsola-Malpighi Hospital University of Bologna, 40138 Bologna, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Mazzanti
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands; Department of Clinical Genetics, Maastricht University Medical Center, PO Box 5800, 6202AZ Maastricht, the Netherlands.
authors.forename: Han G
authors.initials: HG
authors.lastname: Brunner
authors.affiliation: Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: Bakkers
authors.affiliation: Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
authors.forename: Shuo
authors.initials: S
authors.lastname: Lin
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute/NIH, Bethesda, MD 20892, USA. Electronic address: malicdanm@mail.nih.gov.
authors.forename: May Christine V
authors.initials: MC
authors.lastname: Malicdan
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Cornelius F
authors.initials: CF
authors.lastname: Boerkoel
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA; Office of the Clinical Director, National Human Genome Research Institute/NIH, Bethesda, MD 20892, USA. Electronic address: gahlw@helix.nih.gov.
authors.forename: William A
authors.initials: WA
authors.lastname: Gahl
authors.affiliation: Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: de Vries
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
authors.affiliation: Medizinische Fakultät und Universitätsklinikum Magdeburg, Institute of Human Genetics, 39120 Magdeburg, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
authors.affiliation: NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Markello
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D047369:Chromatin Immunoprecipitation; D059472:Exome / Q000235:genetics; D005124:Eye Abnormalities / Q000235:genetics* / Q000473:pathology; D005141:Eyelid Diseases / Q000235:genetics* / Q000473:pathology; D006367:HeLa Cells; D006628:Hirsutism / Q000235:genetics* / Q000473:pathology; D006801:Humans; D006972:Hypertelorism / Q000235:genetics* / Q000473:pathology; D006983:Hypertrichosis / Q000235:genetics* / Q000473:pathology; D008265:Macrostomia / Q000235:genetics* / Q000473:pathology; D008854:Microscopy, Electron; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020125:Mutation, Missense / Q000235:genetics; D010641:Phenotype; D011487:Protein Conformation; D012097:Repressor Proteins / Q000737:chemistry / Q000235:genetics*; D017422:Sequence Analysis, DNA; D012868:Skin Abnormalities / Q000235:genetics* / Q000473:pathology; D051879:Twist-Related Protein 1 / Q000737:chemistry / Q000235:genetics*; D015027:Zebrafish
chemical_list: D012097:Repressor Proteins; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1