De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

M Felicia Basilicata, Ange-Line Bruel, Giuseppe Semplicio, Claudia Isabelle Keller Valsecchi, Tuğçe Aktaş, Yannis Duffourd, Tobias Rumpf, Jenny Morton, Iben Bache, Witold G Szymanski, Christian Gilissen, Olivier Vanakker, Katrin Õunap, Gerhard Mittler, Ineke van der Burgt, Salima El Chehadeh, Megan T Cho, Rolph Pfundt, Tiong Yang Tan, Maria KirchhoffBjörn Menten, Sarah Vergult, Kristin Lindstrom, André Reis, Diana S Johnson, Alan Fryer, Victoria McKay, Richard B Fisher, Christel Thauvin-Robinet, David Francis, Tony Roscioli, Sander Pajusalu, Kelly Radtke, Jaya Ganesh, Han G Brunner, Meredith Wilson, Laurence Faivre, Vera M Kalscheuer, Julien Thevenon, Asifa Akhtar, DDD Study

24 Citations (Scopus)


The etiological spectrum of ultra-rare developmental disorders remains to be fully defined. Chromatin regulatory mechanisms maintain cellular identity and function, where misregulation may lead to developmental defects. Here, we report pathogenic variations in MSL3, which encodes a member of the chromatin-associated male-specific lethal (MSL) complex responsible for bulk histone H4 lysine 16 acetylation (H4K16ac) in flies and mammals. These variants cause an X-linked syndrome affecting both sexes. Clinical features of the syndrome include global developmental delay, progressive gait disturbance, and recognizable facial dysmorphism. MSL3 mutations affect MSL complex assembly and activity, accompanied by a pronounced loss of H4K16ac levels in vivo. Patient-derived cells display global transcriptome alterations of pathways involved in morphogenesis and cell migration. Finally, we use histone deacetylase inhibitors to rebalance acetylation levels, alleviating some of the molecular and cellular phenotypes of patient cells. Taken together, we characterize a syndrome that allowed us to decipher the developmental importance of MSL3 in humans.

Original languageEnglish
JournalNature Genetics
Issue number10
Pages (from-to)1442-1451
Number of pages10
Publication statusPublished - Oct 2018


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