MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis
Authors: Mak Christopher C Y , Doherty Dan , Lin Angela E , Vegas Nancy , Cho Megan T , Viot Géraldine , Dimartino Clémantine , Weisfeld-Adams James D , Lessel Davor , Joss Shelagh , Li Chumei , Gonzaga-Jauregui Claudia , Zarate Yuri A , Ehmke Nadja , Horn Denise , Troyer Caitlin , Kant Sarina G , Lee Youngha , Ishak Gisele E , Leung Gordon , Barone Pritchard Amanda , Yang Sandra , Bend Eric G , Filippini Francesca , Roadhouse Chelsea , Lebrun Nicolas , Mehaffey Michele G , Martin Pierre-Marie , Apple Benjamin , Millan Francisca , Puk Oliver , Hoffer Mariette J V , Henderson Lindsay B , McGowan Ruth , Wentzensen Ingrid M , Pei Steven , Zahir Farah R , Yu Mullin , Gibson William T , Seman Ann , Steeves Marcie , Murrell Jill R , Luettgen Sabine , Francisco Elizabeth , Strom Tim M , Amlie-Wolf Louise , Kaindl Angela M , Wilson William G , Halbach Sara , Basel-Salmon Lina , Lev-El Noa , Denecke Jonas , Vissers Lisenka E L M , Radtke Kelly , Chelly Jamel , Zackai Elaine , Friedman Jan M , Bamshad Michael J , Nickerson Deborah A ,   University of Washington Center for Mendelian Genomics, Reid Russell R , Devriendt Koenraad , Chae Jong-Hee , Stolerman Elliot , McDougall Carey , Powis Zöe , Bienvenu Thierry , Tan Tiong Y , Orenstein Naama , Dobyns William B , Shieh Joseph T , Choi Murim , Waggoner Darrel , Gripp Karen W , Parker Michael J , Stoler Joan , Lyonnet Stanislas , Cormier-Daire Valérie , Viskochil David , Hoffman Trevor L , Amiel Jeanne , Chung Brian H Y , Gordon Christopher T 
Published: November 2019

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.