Journal article

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, Tugce Aktas, Yannis Duffourd, Tobias Rumpf, Jenny Morton, Iben Bache, Witold G Szymanski, Christian Gilissen, Olivier Vanakker, Katrin Ounap, Gerhard Mittler, Ineke Van Der Burgt, Salima El Chehadeh, Megan T Cho, Rolph Pfundt, Tiong Yang Tan, Maria Kirchhoff Show all



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, acc..

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Awarded by Health Innovation Challenge Fund

Awarded by Wellcome Trust Sanger Institute

Awarded by Cambridge South REC

Awarded by Republic of Ireland REC

Awarded by National Heart, Lung and Blood Institute grant

Awarded by German Human Genome Program

Awarded by National Genome Research Network

Awarded by Human Frontier Science Program long-term fellowship

Funding Acknowledgements

We are grateful to the patients and their families for their cooperation and interest in the study. We thank N. Iovino, B. Sheikh, and I. Ilik for critical reading of the manuscript. We also thank C. Pessoa Rodrigues and A. Karoutas for technical help, insightful discussion, and advice. We thank V. Bhardwaj for advice and consulting on RNA-Seq analysis, and S. Kubart, A. Schroer, J. Wirth, and H.-G. Nothwang for help with inversion breakpoint mapping. We thank L. Wells for patient recruitment and clinical data collection. The DDD study presents independent research commissioned by the Health Innovation Challenge Fund (grant number HICF-1009-003), a parallel funding partnership between the Wellcome Trust, Department of Health, and Wellcome Trust Sanger Institute (grant number WT098051). The views expressed in this publication are those of the authors and not necessarily those of the Wellcome Trust or Department of Health. This study has UK Research Ethics Committee (REC) approval (10/H0305/83, granted by the Cambridge South REC; and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research through the Comprehensive Clinical Research Network. This study makes use of DECIPHER (see URLs), which is funded by Wellcome. Sequencing for patient 12 was provided by the Center for Mendelian Genomics at the Broad Institute of MIT and Harvard, and was funded by the National Human Genome Research Institute, National Eye Institute, and National Heart, Lung and Blood Institute grant UM1 HG008900 to D. MacArthur and H. Rehm. This work was supported by CRC992, CRC1140, and CRC746 (awarded to A.A.). It was also supported by the council of Burgundy, German Human Genome Program (grant number 01KW99087) and National Genome Research Network (project numbers 01GR0105 and 01GS08160), awarded to V.M.K. and A.R., respectively. C.I.K.V. was supported by a Human Frontier Science Program long-term fellowship (000233/2014-L).