EGAGenomicsHans vanhttps://ega-archive.org/dacs/EGAC00001000322EGAEGA DAC EGAC00001000322EGAHans.vanBokhoven@radboudumc.nlMöbius syndrome (MBS) is a neurological disorder that is characterized by paralysis of the facial nerves and variable other congenital anomalies. The aetiology of this syndrome has been enigmatic since the initial descriptions by von Graefe in 1880 and by Möbius in 1888, and it has been debated for decades whether MBS has a genetic or a non-genetic aetiology. Here, we report de novo mutations affecting two genes, PLXND1 and REV3L in MBS patients. PLXND1 and REV3L represent totally unrelated pathways involved in hindbrain development: neural migration and DNA translesion synthesis, essential for the replication of endogenously damaged DNA, respectively. Interestingly, analysis of Plxnd1 and Rev3l mutant mice shows that disruption of these separate pathways converge at the facial branchiomotor nucleus, affecting either motoneuron migration or proliferation. The finding that PLXND1 and REV3L mutations are responsible for a proportion of MBS patients suggests that de novo mutations in other genes might account for other MBS patients.De novo mutations in PLXND1 and REV3L cause Möbius syndrome.Tomas-Roca Laura L, Tsaalbi-Shtylik Anastasia A, Jansen Jacob G JG, Singh Manvendra K MK, Epstein Jonathan A JA, Altunoglu Umut U, Verzijl Harriette H, Soria Laura L, van Beusekom Ellen E, Roscioli Tony T, Iqbal Zafar Z, Gilissen Christian C, Hoischen Alexander A, de Brouwer Arjan P M APM, Erasmus Corrie C, Schubert Dirk D, Brunner Han H, Pérez Aytés Antonio A, Marin Faustino F, Marin Faustino F, Aroca Pilar P, Kayserili Hülya H, Carta Arturo A, de Wind Niels N, Padberg George W GW, van Bokhoven Hans Hcluster, WES, Complete Transcriptome, Complete, Complete Transcriptome Sequencing, Exome Sequencings, Complete Exome Sequencings, syndrome associated with disease or disorder, Complete Exome, Complete Exome Sequencing, Whole Transcriptome Sequencing, Exome, syndrome, Clusters, syndromes, syndromic disease or disorder, Sequencing, Symptom, clusters, Exome Sequencing, Whole Exome, NOS" EXACT [SNOMEDCT_2005_07_31:64572001], symptom cluster, Syndromes, "syndrome, Cluster, Symptom Cluster, syndromic disease, Whole, "syndrome" EXACT [MTH:NOCODE], Symptom Clusters, Whole Exome Sequencing, symptom clusters, symptom, Whole Transcriptome, Transcriptome Sequencing, Transcriptome Sequencings, symptom.Mutations, Congenital facial diplegia, Rev, absence or underdevelopment of the 6th and 7th cranial nerves, REV3, Rev3, POLZ, Möbius syndrome, congenital oculofacial paralysis, congenital facial diplegia syndrome., Sez4, PLEXD1rhombencephalon development, Neurological, cluster, Disorders, Materials, syndrome associated with disease or disorder, determination, Laboratory, Mus domesticus, CASP-14, l(3)72Dd, Progress Reports, congenital defects, Todds Paralysis, House Mouse, aplasia, Mandibular Nerves, Plegias, Marginal Mandibular Nerves, Mutations, 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Report, disorder of nervous system, Mini-ICE, Diseases, Genetic Materials, cell nucleus, Palsy, neurological problem, Marginal Mandibular Nerve, Möbius syndrome, desoxyribose nucleic acid, DMbs, DMBS, Genetic Material, Trans-Lesional, atresia, M130, Mus musculus, Alpha Motorneuron, Caspase-14 subunit p10, Nervus Faciali, Sez4, mice, Mandibular Nerve, malformations, Field, Swiss Mouse, Seventh Cranial Nerve, Caspase-14 subunit p19, Nervus Intermedius of Wrisberg, Motor Neurons, MICE, Alpha Motorneurons, clusters, domesticus, Report, Replications, Syndromes, Cluster, Patient, Material, Alpha Motor Neuron, bypass DNA synthesis, anomalies, ds DNA, Cistron, Mypt, Cranial Nerve VIIs, inherited genetic, Mouse, DNA, Alpha, Alpha Motor Neurons, Clinical Finding, Marginal Mandibular Branch, l(3)j3B4, 3.4.22.-, DNS, CG5891, (Deoxyribonucleotide)n, neurologic disorder, Nerve, connatal, Gene, Cranial Nerve, mini-ICE, DMYPT, l(3)S005331b, nervous system disease, motoneuron, syndromic disease or disorder, l(3)j7A1, Deoxyribonucleic acids, Symptoms and Signs, DNA Synthesis, Trans-Lesional DNA, Trans-Lesion DNA Synthesis, neurological disease, Client., Investigative, Deoxyribonucleic Acid, congenital facial diplegia syndrome, House, "syndrome" EXACT [MTH:NOCODE], Nervus Intermedius, symptom clusters, Motoneurons, Trans-Lesional DNA Synthesis, Mus musculus domesticus, Trans-Lesional DNA Replication, defects, Finding, Cranial Nerve VII, Facial Nerves, Mice, Marginal Mandibular, Nervous System, Genetic, congenital oculofacial paralysis, Swiss, Trans Lesion Synthesis, Double Stranded, syndrome, Deoxyribonucleic acid, Neurological Disorder, syndromes, Symptom, MBS, Neurologic, Todd's, Inability to move, NOS" EXACT [SNOMEDCT_2005_07_31:64572001], Trans Lesion DNA Synthesis, Translesional DNA, DNA Replication, Clients, Disorder, Neurological Disorders, Neuron, (Deoxyribonucleotide)m, Investigative Reports, constitutitional genetic, mbs, Disease, Neurologic Disorder, 0573/06, DNAn+1, Nervous System Disorder, Cistrons, DNA Syntheses, Client, l(3)S095304, Translesion DNA, CG32156, Todd's Paralysis, Signs and Symptoms, Mus, agenesis, Symptom Cluster, Research Reports, chemical analysis, Nervous System Disease, ds-DNA, Replication, l(3)S057306b, Todd Paralysis, Trans-Lesion, Translesional Synthesis Pathway, Nervus Facialis, Translesion DNA Replication, Motor Neuron, Nerve of Wrisberg, Wrisberg Nervus Intermedius, Translesional DNA Synthesis, Translesion Synthesis Pathway, neurologic disease, House Mice, Motorneurons, nucleus of neuraxis, Paralysis, Translesion, 0953/04, Palsies, Laboratory Mice, absence or underdevelopment of the 6th and 7th cranial nerves, MYPT1, POLZ, Reports, birth defects, Desoxyribonukleinsaeure, Congenital facial diplegia, Nervous System Disorders, Plegia, assay, Seventh Cranial Nerves, Summary, hereditary, Translesional, Laboratory Mouse, nervous system disorder, Field ReportfalseExome sequencing in Möbius syndromeData Access Committee EGAC00001000322EGAC00001000322960626068067EGAS00001001250EGAD00001001385