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

TitleMN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.
Publication TypeJournal Article
Year of Publication2020
AuthorsC Y Mak, C, Doherty, D, Lin, AE, Vegas, N, Cho, MT, Viot, G, Dimartino, C, Weisfeld-Adams, JD, Lessel, D, Joss, S, Li, C, Gonzaga-Jauregui, C, Zarate, YA, Ehmke, N, Horn, D, Troyer, C, Kant, SG, Lee, Y, Ishak, GE, Leung, G, Pritchard, ABarone, Yang, S, Bend, EG, Filippini, F, Roadhouse, C, Lebrun, N, Mehaffey, MG, Martin, P-M, Apple, B, Millan, F, Puk, O, Hoffer, MJV, Henderson, LB, McGowan, R, Wentzensen, IM, Pei, S, Zahir, FR, Yu, M, Gibson, WT, Seman, A, Steeves, M, Murrell, JR, Luettgen, S, Francisco, E, Strom, TM, Amlie-Wolf, L, Kaindl, AM, Wilson, WG, Halbach, S, Basel-Salmon, L, Lev-El, N, Denecke, J, Vissers, LELM, Radtke, K, Chelly, J, Zackai, E, Friedman, JM, Bamshad, MJ, Nickerson, DA, Reid, RR, Devriendt, K, Chae, J-H, Stolerman, E, McDougall, C, Powis, Z, Bienvenu, T, Tan, TY, Orenstein, N, Dobyns, WB, Shieh, JT, Choi, M, Waggoner, D, Gripp, KW, Parker, MJ, Stoler, J, Lyonnet, S, Cormier-Daire, V, Viskochil, D, Hoffman, TL, Amiel, J, H Y Chung, B, Gordon, CT
Corporate AuthorsUniversity of Washington Center for Mendelian Genomics
Date Published2020 01 01
KeywordsAbnormalities, Multiple, Adolescent, Basilar Artery, Carotid Arteries, Cerebellar Vermis, Cerebellum, Child, Child, Preschool, Cohort Studies, Comparative Genomic Hybridization, Craniofacial Abnormalities, Female, Fibroblasts, Humans, Imaging, Three-Dimensional, Infant, Intellectual Disability, Language Development Disorders, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Nervous System Malformations, Nonsense Mediated mRNA Decay, Polymicrogyria, Real-Time Polymerase Chain Reaction, RNA-Seq, Syndrome, Tomography, X-Ray Computed, Trans-Activators, Tumor Suppressor Proteins, Whole Exome Sequencing, Whole Genome Sequencing

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.

Alternate JournalBrain
PubMed ID31834374
PubMed Central IDPMC7962909
Grant ListU54 HD083091 / HD / NICHD NIH HHS / United States
U01 HG009599 / HG / NHGRI NIH HHS / United States
R01 NS050375 / NS / NINDS NIH HHS / United States
UM1 HG006493 / HG / NHGRI NIH HHS / United States
/ WT / Wellcome Trust / United Kingdom
U24 HG008956 / HG / NHGRI NIH HHS / United States