MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis

Christopher C.Y. Mak, Dan Doherty, Angela E. Lin, Nancy Vegas, Megan T. Cho, Géraldine Viot, Clémantine Dimartino, James D. Weisfeld-Adams, Davor Lessel, Shelagh Joss, Chumei Li, Claudia Gonzaga-Jauregui, Yuri A. Zarate, Nadja Ehmke, Denise Horn, Caitlin Troyer, Sarina G. Kant, Youngha Lee, Gisele E. Ishak, Gordon LeungAmanda Barone Pritchard, Sandra Yang, Eric G. Bend, Francesca Filippini, Chelsea Roadhouse, Nicolas Lebrun, Michele G. Mehaffey, Pierre Marie Martin, Benjamin Apple, Francisca Millan, Oliver Puk, Mariette J.V. Hoffer, Lindsay B. Henderson, Ruth McGowan, Ingrid M. Wentzensen, Steven Pei, Farah R. Zahir, Mullin Yu, William T. Gibson, Ann Seman, Marcie Steeves, Jill R. Murrell, Sabine Luettgen, Elizabeth Francisco, Tim M. Strom, Louise Amlie-Wolf, Angela M. Kaindl, William G. Wilson, Sara Halbach, Lina Basel-Salmon, Noa Lev-El, Jonas Denecke, Lisenka E.L.M. Vissers, Kelly Radtke, Jamel Chelly, Elaine Zackai, Jan M. Friedman, Michael J. Bamshad, Deborah A. Nickerson, Russell R. Reid, Koenraad Devriendt, Jong Hee Chae, Elliot Stolerman, Carey McDougall, Zöe Powis, Thierry Bienvenu, Tiong Y. Tan, Naama Orenstein, William B. Dobyns, Joseph T. Shieh, Murim Choi, Darrel Waggoner, Karen W. Gripp, Michael J. Parker, Joan Stoler, Stanislas Lyonnet, Valérie Cormier-Daire, David Viskochil, Trevor L. Hoffman, Jeanne Amiel, Brian H.Y. Chung, Christopher T. Gordon

Research output: Contribution to journalArticlepeer-review


MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions encompassing MN1 have been reported in individuals with variable neurodevelopmental anomalies and non-specific facial features. We identified a cluster of de novo truncating mutations in MN1 in a cohort of 23 individuals with strikingly similar dysmorphic facial features, especially midface hypoplasia, and intellectual disability with severe expressive language delay. Imaging revealed an atypical form of rhombencephalosynapsis, a distinctive brain malformation characterized by partial or complete loss of the cerebellar vermis with fusion of the cerebellar hemispheres, in 8/10 individuals. Rhombencephalosynapsis has no previously known definitive genetic or environmental causes. Other frequent features included perisylvian polymicrogyria, abnormal posterior clinoid processes and persistent trigeminal artery. MN1 is encoded by only two exons. All mutations, including the recurrent variant p.Arg1295∗ observed in 8/21 probands, fall in the terminal exon or the extreme 3′ region of exon 1, and are therefore predicted to result in escape from nonsense-mediated mRNA decay. This was confirmed in fibroblasts from three individuals. We propose that the condition described here, MN1 C-terminal truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominantly acting C-terminally truncated MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door to understanding the biological mechanisms underlying rhombencephalosynapsis.

Original languageEnglish
Pages (from-to)55-68
Number of pages14
Issue number1
StatePublished - 1 Jan 2020


  • MCTT syndrome
  • MN1
  • craniofacial development
  • intellectual disability
  • rhombencephalosynapsis


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