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... 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
Boschann, F.; Stuurman, K.E.; Bruin, C. de; Slegtenhorst, M. van; Duyvenvoorde, H.A. van; Kant, S.G.; Ehmke, N. 2019
Catel-Manzke syndrome, also known as micrognathia-digital-syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre-Robin sequence and... Show moreCatel-Manzke syndrome, also known as micrognathia-digital-syndrome, is a rare autosomal recessive disorder characterized by the combination of the two cardinal features Pierre-Robin sequence and bilateral hyperphalangy leading to ulnar clinodactyly (ulnar curvature of the phalanges) and radial deviation (radial angulation at the metacarpophalangeal joint) of the index fingers. Individuals without one of these major hallmarks or with additional hand malformations have been described as atypical or Catel-Manzke-like syndrome. Biallelic TGDS pathogenic variants have thus far been detected in eight individuals with typical Catel-Manzke syndrome and in one fetus with additional features. Here we report on two individuals with TGDS pathogenic variants who presented with mild radial deviation and ulnar clinodactyly of the index fingers but without radiologic signs of hyperphalangy. Furthermore, both individuals have disproportionate short stature, a feature that has not yet been associated with Catel-Manzke syndrome. Our data broaden the phenotypic spectrum of TGDS-associated Catel-Manzke syndrome and expand the indication for diagnostic testing. Show less
Menke, L.A.; Belzen, M.J. van; Alders, M.; Cristofoli, F.; Ehmke, N.; Fergelot, P.; ... ; DDD Study 2016
