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

Shannon Marchegiani, Taylor Davis, Federico Tessadori, Gijs van Haaften, Francesco Brancati, Alexander Hoischen, Haigen Huang, Elise Valkanas, Barbara Pusey, Denny Schanze, Hanka Venselaar, Anneke T. Vulto-van Silfhout, Lynne A. Wolfe, Cynthia J. Tifft, Patricia M. Zerfas, Giovanna Zambruno, Ariana Kariminejad, Farahnaz Sabbagh-Kermani, Janice Lee, Maria G. TsokosChyi-Chia R. Lee, Victor Ferraz, Eduarda Morgana da Silva, Cathy A. Stevens, Nathalie Roche, Oliver Bartsch, Peter Farndon, Eva Bermejo-Sanchez, Brian P. Brooks, Valerie Maduro, Bruno Dallapiccola, Feliciano J. Ramos, Hon-Yin Brian Chung, Cedric Le Caignec, Fabiana Martins, Witold K. Jacyk, Laura Mazzanti, Han G. Brunner, Jeroen Bakkers, Shuo Lin, May Christine V. Malicdan*, Cornelius F. Boerkoel, William A. Gahl, Bert B. A. de Vries, Mieke M. van Haelst, Martin Zenker, Thomas C. Markello

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


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. TW1ST2 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-1'WIST2 in HeLa cells. Comparison of wild-type and mutant TW1ST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TW1ST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
Original languageEnglish
Pages (from-to)99-110
JournalAmerican Journal of Human Genetics
Issue number1
Publication statusPublished - 2 Jul 2015

Cite this