@article {770, title = {MN1 C-terminal truncation syndrome is a novel neurodevelopmental and craniofacial disorder with partial rhombencephalosynapsis.}, journal = {Brain}, volume = {143}, year = {2020}, month = {2020 01 01}, pages = {55-68}, 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{\textquoteright} 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.

}, keywords = {Abnormalities, 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}, issn = {1460-2156}, doi = {10.1093/brain/awz379}, author = {Mak, Christopher C Y and Doherty, Dan and Lin, Angela E and Vegas, Nancy and Cho, Megan T and Viot, G{\'e}raldine and Dimartino, Cl{\'e}mantine and Weisfeld-Adams, James D and Lessel, Davor and Joss, Shelagh and Li, Chumei and Gonzaga-Jauregui, Claudia and Zarate, Yuri A and Ehmke, Nadja and Horn, Denise and Troyer, Caitlin and Kant, Sarina G and Lee, Youngha and Ishak, Gisele E and Leung, Gordon and Barone Pritchard, Amanda and Yang, Sandra and Bend, Eric G and Filippini, Francesca and Roadhouse, Chelsea and Lebrun, Nicolas and Mehaffey, Michele G and Martin, Pierre-Marie and Apple, Benjamin and Millan, Francisca and Puk, Oliver and Hoffer, Mariette J V and Henderson, Lindsay B and McGowan, Ruth and Wentzensen, Ingrid M and Pei, Steven and Zahir, Farah R and Yu, Mullin and Gibson, William T and Seman, Ann and Steeves, Marcie and Murrell, Jill R and Luettgen, Sabine and Francisco, Elizabeth and Strom, Tim M and Amlie-Wolf, Louise and Kaindl, Angela M and Wilson, William G and Halbach, Sara and Basel-Salmon, Lina and Lev-El, Noa and Denecke, Jonas and Vissers, Lisenka E L M and Radtke, Kelly and Chelly, Jamel and Zackai, Elaine and Friedman, Jan M and Bamshad, Michael J and Nickerson, Deborah A and Reid, Russell R and Devriendt, Koenraad and Chae, Jong-Hee and Stolerman, Elliot and McDougall, Carey and Powis, Z{\"o}e and Bienvenu, Thierry and Tan, Tiong Y and Orenstein, Naama and Dobyns, William B and Shieh, Joseph T and Choi, Murim and Waggoner, Darrel and Gripp, Karen W and Parker, Michael J and Stoler, Joan and Lyonnet, Stanislas and Cormier-Daire, Val{\'e}rie and Viskochil, David and Hoffman, Trevor L and Amiel, Jeanne and Chung, Brian H Y and Gordon, Christopher T} } @article {287, title = {Mutations in VRK1 associated with complex motor and sensory axonal neuropathy plus microcephaly.}, journal = {JAMA Neurol}, volume = {70}, year = {2013}, month = {2013 Dec}, pages = {1491-8}, abstract = {

IMPORTANCE: Patients with rare diseases and complex clinical presentations represent a challenge for clinical diagnostics. Genomic approaches are allowing the identification of novel variants in genes for very rare disorders, enabling a molecular diagnosis. Genomics is also revealing a phenotypic expansion whereby the full spectrum of clinical expression conveyed by mutant alleles at a locus can be better appreciated.

OBJECTIVE: To elucidate the molecular cause of a complex neuropathy phenotype in 3 patients by applying genomic sequencing strategies.

DESIGN, SETTING, AND PARTICIPANTS: Three affected individuals from 2 unrelated families presented with a complex neuropathy phenotype characterized by axonal sensorimotor neuropathy and microcephaly. They were recruited into the Centers for Mendelian Genomics research program to identify the molecular cause of their phenotype. Whole-genome, targeted whole-exome sequencing, and high-resolution single-nucleotide polymorphism arrays were performed in genetics clinics of tertiary care pediatric hospitals and biomedical research institutions.

MAIN OUTCOMES AND MEASURES: Whole-genome and whole-exome sequencing identified the variants responsible for the patients{\textquoteright} clinical phenotype.

RESULTS: We identified compound heterozygous alleles in 2 affected siblings from 1 family and a homozygous nonsense variant in the third unrelated patient in the vaccinia-related kinase 1 gene (VRK1). In the latter subject, we found a common haplotype on which the nonsense mutation occurred and that segregates in the Ashkenazi Jewish population.

CONCLUSIONS AND RELEVANCE: We report the identification of disease-causing alleles in 3 children from 2 unrelated families with a previously uncharacterized complex axonal motor and sensory neuropathy accompanied by severe nonprogressive microcephaly and cerebral dysgenesis. Our data raise the question of whether VRK1 mutations disturb cell cycle progression and may result in apoptosis of cells in the nervous system. The application of unbiased genomic approaches allows the identification of potentially pathogenic mutations in unsuspected genes in highly genetically heterogeneous and uncharacterized neurological diseases.

}, keywords = {Child, Child, Preschool, DNA Mutational Analysis, Female, Genotype, Hereditary Sensory and Motor Neuropathy, Humans, Infant, Intracellular Signaling Peptides and Proteins, Magnetic Resonance Imaging, Male, Microcephaly, Mutation, Neural Conduction, Polymorphism, Single Nucleotide, Protein-Serine-Threonine Kinases}, issn = {2168-6157}, doi = {10.1001/jamaneurol.2013.4598}, author = {Gonzaga-Jauregui, Claudia and Lotze, Timothy and Jamal, Leila and Penney, Samantha and Campbell, Ian M and Pehlivan, Davut and Hunter, Jill V and Woodbury, Suzanne L and Raymond, Gerald and Adesina, Adekunle M and Jhangiani, Shalini N and Reid, Jeffrey G and Muzny, Donna M and Boerwinkle, Eric and Lupski, James R and Gibbs, Richard A and Wiszniewski, Wojciech} }