Systematic phenotype and genotype characterization of Moebius syndrome
Purpose: To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction. Methods: We applied strict diagnostic criteria and conducted clinical phenotyping of 1...
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2025-01-01
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| author | Bryn D. Webb Julie A. Jurgens Narisu Narisu Zhongyang Zhang Brenda J. Barry Carol Van Ryzin Lori L. Bonnycastle Wai-Man Chan Tingfen Yan Silvio Alessandro Di Gioia Amy J. Swift Sarah E. MacKinnon Darren T. Oystreck Janet C. Rucker Tamiesha Frempong Mary C. Whitman Edmond J. FitzGibbon Janice S. Lee Ke Hao Caroline Andrews Monica Erazo Flavia M. Facio Sherin Shaaban Thomas P. Naidich Peter S. Chines Tanya J. Lehky Camilo Toro Andrea L. Gropman John A. Butman Christopher K. Zalewski Carmen C. Brewer Audrey Thurm Joseph Snow Scott M. Paul Brian P. Brooks Carlo Pierpaoli Caroline D. Robson David G. Hunter Francis S. Collins Ethylin Wang Jabs Elizabeth C. Engle Irini Manoli |
| author_facet | Bryn D. Webb Julie A. Jurgens Narisu Narisu Zhongyang Zhang Brenda J. Barry Carol Van Ryzin Lori L. Bonnycastle Wai-Man Chan Tingfen Yan Silvio Alessandro Di Gioia Amy J. Swift Sarah E. MacKinnon Darren T. Oystreck Janet C. Rucker Tamiesha Frempong Mary C. Whitman Edmond J. FitzGibbon Janice S. Lee Ke Hao Caroline Andrews Monica Erazo Flavia M. Facio Sherin Shaaban Thomas P. Naidich Peter S. Chines Tanya J. Lehky Camilo Toro Andrea L. Gropman John A. Butman Christopher K. Zalewski Carmen C. Brewer Audrey Thurm Joseph Snow Scott M. Paul Brian P. Brooks Carlo Pierpaoli Caroline D. Robson David G. Hunter Francis S. Collins Ethylin Wang Jabs Elizabeth C. Engle Irini Manoli |
| author_sort | Bryn D. Webb |
| collection | DOAJ |
| description | Purpose: To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction. Methods: We applied strict diagnostic criteria and conducted clinical phenotyping of 149 individuals with MBS. Subsequently, we performed exome and/or genome sequencing on 67 of these individuals and 117 unaffected family members. Results: All 149 individuals had sporadic MBS, with no recurrence within or across generations. Common co-occurring phenotypes included tongue hypoplasia (81.9%), micrognathia (66.4%), congenital talipes equinovarus (42.3%), major limb anomalies (31.5%), intellectual disability (30.9%), sleep difficulties (22.8%), and Poland anomaly (14.1%). Filtering for rare de novo or autosomal recessive single-nucleotide, insertion/deletion, and structural variants in the sequenced cohort yielded 173 single-nucleotide variant/indels in 113 genes. Although we prioritized 7 candidate genes with de novo variants and 5 with biallelic variants, no compelling recurrently mutated genes were identified. Similarly, we found no convincing variants in 2 putative genes previously implicated in MBS: PLXND1 (HGNC:9107) and REV3L (HGNC:9968). Conclusion: We did not identify a strong or unifying germline genetic etiology for MBS. Future studies may explore alternative causes, including environmental exposures, somatic variants, and/or complex inheritance patterns affecting brainstem and organ embryogenesis. |
| format | Article |
| id | doaj-art-e871d5e94d2146df9e0691f063de070a |
| institution | Kabale University |
| issn | 2949-7744 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
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| series | Genetics in Medicine Open |
| spelling | doaj-art-e871d5e94d2146df9e0691f063de070a2025-08-20T03:30:02ZengElsevierGenetics in Medicine Open2949-77442025-01-01310343710.1016/j.gimo.2025.103437Systematic phenotype and genotype characterization of Moebius syndromeBryn D. Webb0Julie A. Jurgens1Narisu Narisu2Zhongyang Zhang3Brenda J. Barry4Carol Van Ryzin5Lori L. Bonnycastle6Wai-Man Chan7Tingfen Yan8Silvio Alessandro Di Gioia9Amy J. Swift10Sarah E. MacKinnon11Darren T. Oystreck12Janet C. Rucker13Tamiesha Frempong14Mary C. Whitman15Edmond J. FitzGibbon16Janice S. Lee17Ke Hao18Caroline Andrews19Monica Erazo20Flavia M. Facio21Sherin Shaaban22Thomas P. Naidich23Peter S. Chines24Tanya J. Lehky25Camilo Toro26Andrea L. Gropman27John A. Butman28Christopher K. Zalewski29Carmen C. Brewer30Audrey Thurm31Joseph Snow32Scott M. Paul33Brian P. Brooks34Carlo Pierpaoli35Caroline D. Robson36David G. Hunter37Francis S. Collins38Ethylin Wang Jabs39Elizabeth C. Engle40Irini Manoli41Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Pediatrics, University of Wisconsin School of Medicine and Public Health, Madison, WIF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Neurology, Boston Children’s Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MACenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NYF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Neurology, Boston Children’s Hospital, Boston, MA; Howard Hughes Medical Institute, Chevy Chase, MDMetabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Neurology, Boston Children’s Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA; Howard Hughes Medical Institute, Chevy Chase, MDCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Neurology, Boston Children’s Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA; Regeneron Pharmaceuticals, Tarrytown, NYCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDDepartment of Ophthalmology, Boston Children’s Hospital, Boston, MA; Department of Ophthalmology, Harvard Medical School, Boston, MADepartment of Ophthalmology, Boston Children’s Hospital, Boston, MA; Eye Clinic, IWK Health Centre, Halifax, NS, Canada; Clinical Vision Science, Faculty of Health, Dalhousie University, Halifax, NS, CanadaDepartment of Neurology, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NY; Deparment of Neurology, New York University Grossman School of Medicine, New York, NY; Department of Ophthalmology, New York University Grossman School of Medicine, New York, NYDepartment of Ophthalmology, Icahn School of Medicine at Mount Sinai, New York, NYF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Ophthalmology, Boston Children’s Hospital, Boston, MA; Department of Ophthalmology, Harvard Medical School, Boston, MALaboratory of Sensorimotor Research, National Eye Institute, National Institutes of Health, Bethesda, MDCraniofacial Anomalies and Regeneration Section, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MDDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NYDepartment of Neurology, Boston Children’s Hospital, Boston, MADepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NYCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDF.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Neurology, Boston Children’s Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Department of Pathology, University of Utah School of Medicine, Salt Lake City, UTDepartment of Diagnostic, Molecular, and Interventional Radiology, Icahn School of Medicine at Mount Sinai, New York, NYCenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDElectromyography Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MDUndiagnosed Disease Program, Office of the Clinical Director, National Human Genome Research Institute, National Institutes of Health, Bethesda, MDDivision of Neurogenetics, Center for Neuroscience and Behavioral Medicine, Children’s National Health System, Washington, DCRadiology & Imaging Sciences Department, Clinical Center, National Institutes of Health, Bethesda, MDOtolaryngology Branch, Audiology Unit, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MDOtolaryngology Branch, Audiology Unit, National Institute on Deafness and Other Communication Disorders, National Institutes of Health, Bethesda, MDPediatrics and Developmental Neuroscience Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, MDOffice of the Clinical Director, National Institute of Mental Health, National Institutes of Health, Bethesda, MDRehabilitation Medicine Department, Clinical Center, National Institutes of Health, Bethesda, MDOphthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MDLaboratory on Quantitative Medical Imaging, National Institute of Biomedical Imaging and Bioengineering, National Institutes of Health, Bethesda, MDDivision of Neuroradiology, Department of Radiology, Boston Children's Hospital, Boston, MA; Department of Radiology, Harvard Medical School, Boston, MADepartment of Ophthalmology, Boston Children’s Hospital, Boston, MA; Department of Ophthalmology, Harvard Medical School, Boston, MACenter for Precision Health Research, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; Francis S. Collins, BG 50, RM 5312, 50 South Dr, Bethesda, MD 20892-8004.Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Cell, Developmental, and Regenerative Biology, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY; Department of Clinical Genomics, Mayo Clinic, Rochester, MN; Ethylin Wang Jabs, Mayo Clinic, 200 First St, Rochester, MN 55905.F.M. Kirby Neurobiology Center, Boston Children’s Hospital, Boston, MA; Department of Neurology, Boston Children’s Hospital, Boston, MA; Department of Neurology, Harvard Medical School, Boston, MA; Broad Institute of MIT and Harvard, Cambridge, MA; Howard Hughes Medical Institute, Chevy Chase, MD; Department of Ophthalmology, Boston Children’s Hospital, Boston, MA; Department of Ophthalmology, Harvard Medical School, Boston, MA; Elizabeth C. Engle, Boston Children's Hospital, Engle Lab-CLS14076 (BCH3149), 3 Blackfan St, Boston, MA 02115.Metabolic Medicine Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD; Correspondence and requests for materials should be addressed to Irini Manoli, BG 10, RM 7N248B, 10 Center Dr, Bethesda, MD 20892-1646.Purpose: To explore the phenotypic spectrum and genetic etiologies of Moebius Syndrome (MBS), a rare neurological disorder defined by congenital, nonprogressive facial weakness and limitations in ocular abduction. Methods: We applied strict diagnostic criteria and conducted clinical phenotyping of 149 individuals with MBS. Subsequently, we performed exome and/or genome sequencing on 67 of these individuals and 117 unaffected family members. Results: All 149 individuals had sporadic MBS, with no recurrence within or across generations. Common co-occurring phenotypes included tongue hypoplasia (81.9%), micrognathia (66.4%), congenital talipes equinovarus (42.3%), major limb anomalies (31.5%), intellectual disability (30.9%), sleep difficulties (22.8%), and Poland anomaly (14.1%). Filtering for rare de novo or autosomal recessive single-nucleotide, insertion/deletion, and structural variants in the sequenced cohort yielded 173 single-nucleotide variant/indels in 113 genes. Although we prioritized 7 candidate genes with de novo variants and 5 with biallelic variants, no compelling recurrently mutated genes were identified. Similarly, we found no convincing variants in 2 putative genes previously implicated in MBS: PLXND1 (HGNC:9107) and REV3L (HGNC:9968). Conclusion: We did not identify a strong or unifying germline genetic etiology for MBS. Future studies may explore alternative causes, including environmental exposures, somatic variants, and/or complex inheritance patterns affecting brainstem and organ embryogenesis.http://www.sciencedirect.com/science/article/pii/S2949774425014761Congenital facial weaknessCranial nerveExome sequencingGenome sequencingMoebius syndrome |
| spellingShingle | Bryn D. Webb Julie A. Jurgens Narisu Narisu Zhongyang Zhang Brenda J. Barry Carol Van Ryzin Lori L. Bonnycastle Wai-Man Chan Tingfen Yan Silvio Alessandro Di Gioia Amy J. Swift Sarah E. MacKinnon Darren T. Oystreck Janet C. Rucker Tamiesha Frempong Mary C. Whitman Edmond J. FitzGibbon Janice S. Lee Ke Hao Caroline Andrews Monica Erazo Flavia M. Facio Sherin Shaaban Thomas P. Naidich Peter S. Chines Tanya J. Lehky Camilo Toro Andrea L. Gropman John A. Butman Christopher K. Zalewski Carmen C. Brewer Audrey Thurm Joseph Snow Scott M. Paul Brian P. Brooks Carlo Pierpaoli Caroline D. Robson David G. Hunter Francis S. Collins Ethylin Wang Jabs Elizabeth C. Engle Irini Manoli Systematic phenotype and genotype characterization of Moebius syndrome Genetics in Medicine Open Congenital facial weakness Cranial nerve Exome sequencing Genome sequencing Moebius syndrome |
| title | Systematic phenotype and genotype characterization of Moebius syndrome |
| title_full | Systematic phenotype and genotype characterization of Moebius syndrome |
| title_fullStr | Systematic phenotype and genotype characterization of Moebius syndrome |
| title_full_unstemmed | Systematic phenotype and genotype characterization of Moebius syndrome |
| title_short | Systematic phenotype and genotype characterization of Moebius syndrome |
| title_sort | systematic phenotype and genotype characterization of moebius syndrome |
| topic | Congenital facial weakness Cranial nerve Exome sequencing Genome sequencing Moebius syndrome |
| url | http://www.sciencedirect.com/science/article/pii/S2949774425014761 |
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