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
JournalBrain
Volume143
Issue1
Pagination55-68
Date Published2020 01 01
ISSN1460-2156
Abstract

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.

DOI10.1093/brain/awz379
Alternate JournalBrain
PubMed ID31834374
Grant ListU01 HG009599 / HG / NHGRI NIH HHS / United States
U54 HD083091 / HD / NICHD NIH HHS / United States
U54 HG006493 / HG / NHGRI NIH HHS / United States