2. Academic Validation
  3. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

  • Am J Hum Genet. 2015 Jul 2;97(1):99-110. doi: 10.1016/j.ajhg.2015.05.017.
Shannon Marchegiani 1,  Taylor Davis 2,  Federico Tessadori 3,  Gijs van Haaften 4,  Francesco Brancati 5,  Alexander Hoischen 6,  Haigen Huang 7,  Elise Valkanas 2,  Barbara Pusey 2,  Denny Schanze 8,  Hanka Venselaar 6,  Anneke T Vulto-van Silfhout 6,  Lynne A Wolfe 9,  Cynthia J Tifft 9,  Patricia M Zerfas 10,  Giovanna Zambruno 11,  Ariana Kariminejad 12,  Farahnaz Sabbagh-Kermani 13,  Janice Lee 14,  Maria G Tsokos 15,  Chyi-Chia R Lee 15,  Victor Ferraz 16,  Eduarda Morgana da Silva 16,  Cathy A Stevens 17,  Nathalie Roche 18,  Oliver Bartsch 19,  Peter Farndon 20,  Eva Bermejo-Sanchez 21,  Brian P Brooks 22,  Valerie Maduro 2,  Bruno Dallapiccola 23,  Feliciano J Ramos 24,  Hon-Yin Brian Chung 25,  Cédric Le Caignec 26,  Fabiana Martins 27,  Witold K Jacyk 28,  Laura Mazzanti 29,  Han G Brunner 30,  Jeroen Bakkers 3,  Shuo Lin 7,  May Christine V Malicdan 31,  Cornelius F Boerkoel 2,  William A Gahl 32,  Bert B A de Vries 6,  Mieke M van Haelst 4,  Martin Zenker 8,  Thomas C Markello 2
Affiliations

Affiliations

  • 1 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.
  • 2 NIH Undiagnosed Diseases Program, Common Fund, Office of the Director, NIH and National Human Genome Research Institute, NIH, Bethesda, MD 20892, USA.
  • 3 Hubrecht Institute-KNAW and University Medical Centre Utrecht, 3584 CT Utrecht, the Netherlands.
  • 4 Department of Medical Genetics, University Medical Center Utrecht, 3508 AB Utrecht, the Netherlands.
  • 5 Department of Medical, Oral, and Biotechnological Sciences, University of G. d' Annunzio Chieti and Pescara, Chieti 66100, Italy.
  • 6 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands.
  • 7 Department of Molecular, Cell, and Developmental Biology, University of California, Los Angeles, Los Angeles, CA 90095, USA.
  • 8 Medizinische Fakultät und Universitätsklinikum Magdeburg, Institute of Human Genetics, 39120 Magdeburg, Germany.
  • 9 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.
  • 10 Office of Research Services, Division of Veterinary Resources, NIH, Bethesda, MD 20892, USA.
  • 11 Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell'Immacolata IDI-IRCCS, Rome 00167, Italy.
  • 12 Kariminejad-Najmabadi Pathology and Genetics Center, Tehran 14667, Iran.
  • 13 Kerman University of Medical Sciences, Kerman 76175, Iran.
  • 14 National Institute of Dental and Craniofacial Research, NIH, Bethesda, MD 20892, USA.
  • 15 Laboratory of Pathology, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
  • 16 Departamento de Genetica, Faculdade de Medicina de Ribeirao Preto, Universidade de Sao Paulo, Sao Paulo 14049, Brazil.
  • 17 Department of Medical Genetics, T.C. Thompson Children's Hospital, Chattanooga, TN 37403, USA.
  • 18 Department of Plastic and Reconstructive Surgery, University Hospital of Ghent, Ghent 9000, Belgium.
  • 19 Institute of Human Genetics, Johannes Gutenberg University, Mainz 55131, Germany.
  • 20 Clinical Genetics Unit, Birmingham Women's Healthcare Trust, Birmingham B15 2TG, UK.
  • 21 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.
  • 22 Unit on Pediatric, Developmental, and Genetic Eye Disease, National Eye Institute, NIH, Bethesda, MD 20892, USA.
  • 23 Department of Medical Genetics, Bambino Gesù Children's Hospital, IRCCS, Rome 00165, Italy.
  • 24 Unidad de Genética Médica, Servicio de Pediatría, GCV-CIBERER Hospital Clínico Universitario "Lozano Blesa," Facultad de Medicina, Universidad de Zaragoza, 50009 Zaragoza, Spain.
  • 25 Department of Paediatrics and Adolescent Medicine, Centre for Genomic Sciences, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
  • 26 Service de genetique medicale, CHU Nantes, 44093 Nantes, France and Inserm, UMR957, Faculté de Médecine, 44093 Nantes, France.
  • 27 Special Care Dentistry Center, Department of Stomatology, School of Dentistry, University of São Paulo, São Paulo 05508-070, Brazil.
  • 28 Department of Dermatology, University of Pretoria, Pretoria 0028, Republic of South Africa.
  • 29 Department of Pediatrics, S. Orsola-Malpighi Hospital University of Bologna, 40138 Bologna, Italy.
  • 30 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.
  • 31 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.
  • 32 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.
PMID: 26119818 DOI: 10.1016/j.ajhg.2015.05.017
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.

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