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

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.

A three-year follow-up study evaluating clinical utility of exome sequencing and diagnostic potential of reanalysis

“…Lastly, the diagnosis of individual U036 was confirmed through international collaboration for new syndrome discovery: MN1 C-terminal truncation syndrome, where 23 individuals who harbor truncating variants at C-terminal of MN1 gene were found to share strikingly similar neurodevelopmental and craniofacial features 51 . It is postulated that these C-terminal truncating variants have escaped nonsense-mediated mRNA decay, thus creating a gain-of-function effect that increased protein stability, diminished cell proliferation, and enhanced MN1 aggregation 51 , 52 .…”

The features of novel miRNAs interaction with mRNA candidate genes having trinucleotide repeats in coding sequences and untranslated regions

“…MN1 C-Terminal Truncation (MCTT) syndrome is a genetic disorder caused by an MN1 gene alteration. A genetic modification of the MN1 gene was related to intellectual disability (ID) [20].…”

Clinical and molecular evaluation of 13 Brazilian patients with Gomez‐López‐Hernández syndrome

“…In the last step, variants in ACP2 were analyzed because an Acp2 ‐ knockout mouse model had a similar phenotype to GLHS (Mannan et al, 2004). We also analyzed variants in MN1 because loss‐of‐function variants in MN1 were identified in patients with RES and dysmorphic features such as mid‐face hypoplasia (Mak et al, 2020).…”