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

Mak, C.C.Y.; Doherty, D.; Lin, A.E.; Vegas, N.; Cho, M.T.; Viot, G.; Dimartino, C.; Weisfeld-Adams, J.D.; Lessel, D.; Joss, S.; Li, C.M.; Gonzaga-Jauregui, C.; Zarate, Y.A.; Ehmke, N.; Horn, D.; Troyer, C.; Kant, S.G.; Lee, Y.; Ishak, G.E.; Leung, G.; Pritchard, A.B.; Yang, S.; Bend, E.G.; Filippini, F.; Roadhouse, C.; Lebrun, N.; Mehaffey, M.G.; Martin, P.M.; Apple, B.; Millan, F.; Puk, O.; Hoffer, M.J.V.; Henderson, L.B.; McGowan, R.; Wentzensen, I.M.; Pei, S.; Zahir, F.R.; Yu, M.L.; Gibson, W.T.; Seman, A.; Steeves, M.; Murrell, J.R.; Luettgen, S.; Francisco, E.; Strom, T.M.; Amlie-Wolf, L.; Kaindl, A.M.; Wilson, W.G.; Halbach, S.; Basel-Salmon, L.; Lev-El, N.; Denecke, J.; Vissers, L.E.L.M.; Radtke, K.; Chelly, J.; Zackai, E.; Friedman, J.M.; Bamshad, M.J.; Nickerson, D.A.; Reid, R.R.; Devriendt, K.; Chae, J.H.; Stolerman, E.; McDougall, C.; Powis, Z.; Bienvenu, T.; Tan, T.Y.; Orenstein, N.; Dobyns, W.B.; Shieh, J.T.; Choi, M.; Waggoner, D.; Gripp, K.W.; Parker, M.J.; Stoler, J.; Lyonnet, S.; Cormier-Daire, V.; Viskochil, D.; Hoffman, T.L.; Amiel, J.; Chung, B.H.Y.; Gordon, C.T.; Univ Washington Ctr

doi:doi:10.1093/brain/awz379

Persistent URL of this record https://hdl.handle.net/1887/3184979

View statistics

In Collections

This item can be found in the following collections:

Medicine / Leiden University Medical Centre (LUMC)

Mak, C.C.Y.; Doherty, D.; Lin, A.E.; Vegas, N.; Cho, M.T.; Viot, G.; ... ; Univ Washington Ctr (2020)

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

Article / Letter to editor

MN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions cricoinp:wiing, MN1 have here reported in individuals with variable neurodevclop-mental 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 8/21 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,...Show moreMN1 encodes a transcriptional co-regulator without homology to other proteins, previously implicated in acute myeloid leukaemia and development of the palate. Large deletions cricoinp:wiing, MN1 have here reported in individuals with variable neurodevclop-mental 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 8/21 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 eNon 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-termirim truncation (MCTT) syndrome, is not due to MN1 haploinsufficiency but rather is the result of dominandy acting C-terminally MN1 protein. Our data show that MN1 plays a critical role in human craniofacial and brain development, and opens the door t understanding the biological mechanisms underlying rhombencephalosynapsis.Show less

MN1

MCTT syndrome

craniofacial development

intellectual disability

rhombencephalosynapsis