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TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy

Abstract

Microtubules are formed from heterodimers of alpha- and beta-tubulin, each of which has multiple isoforms encoded by separate genes. Pathogenic missense variants in multiple different tubulin isoforms cause brain malformations. Missense mutations in TUBB3, which encodes the neuron-specific beta-tubulin isotype, can cause congenital fibrosis of the extraocular muscles type 3 (CFEOM3) and/or malformations of cortical development, with distinct genotype–phenotype correlations. Here, we report fourteen individuals from thirteen unrelated families, each of whom harbors the identical NM_006086.4 (TUBB3):c.785G>A (p.Arg262His) variant resulting in a phenotype we refer to as the TUBB3 R262H syndrome. The affected individuals present at birth with ptosis, ophthalmoplegia, exotropia, facial weakness, facial dysmorphisms, and, in most cases, distal congenital joint contractures, and subsequently develop intellectual disabilities, gait disorders with proximal joint contractures, Kallmann syndrome (hypogonadotropic hypogonadism and anosmia), and a progressive peripheral neuropathy during the first decade of life. Subsets may also have vocal cord paralysis, auditory dysfunction, cyclic vomiting, and/or tachycardia at rest. All fourteen subjects share a recognizable set of brain malformations, including hypoplasia of the corpus callosum and anterior commissure, basal ganglia malformations, absent olfactory bulbs and sulci, and subtle cerebellar malformations. While similar, individuals with the TUBB3 R262H syndrome can be distinguished from individuals with the TUBB3 E410K syndrome by the presence of congenital and acquired joint contractures, an earlier onset peripheral neuropathy, impaired gait, and basal ganglia malformations.

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Funding

Funding provided by the NIH 5K08EY027850 (MCW), 5K12EY016335 (MCW), NIH U01HD079068 (EWJ, IM, ECE); the Moebius Syndrome Foundation (FMF, BDW); NIH intramural projects ZIA DE000746-06 (JSL), ZIA HD008919 (AD), ZIA HG200389-08 (IM, FSC), NIDCD Intramural Research Program (CZ, KAK, CCB), NIH Director’s Common Fund to the NIH Undiagnosed Diseases Program (PRL, CT), Region Stockholm ALF, Grant SLL 500306 (ET), Children’s Hospital Ophthalmology Foundation (MCW), Boston Children’s Hospital Intellectual and Developmental Disabilities Research Center (NICHD 1U54HD090255). ECE is a Howard Hughes Medical Institute Investigator. ET thanks Clinical Genomics, SciLifeLab, Stockholm for excellent collaboration in development of clinical WGS analyses.

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MCW, BJB, IM, and ECE conceptualized the experimental design. W-MC performed targeted sequencing. IM and FSC supervised and CVR and FMF coordinated the NIH phenotyping studies. IM, TJL, AT, CZ, KAK, CB, KA, JSL, AD, EF, PRL, CT, and SMP conducted phenotyping studies at NIH. BDW, EWJ, SM, DGH, IM, and ECE conducted phenotyping studies at Moebius Syndrome Foundation Meetings. BJB coordinated non-NIH and non-foundation phenotyping studies. CDR and ECE interpreted the MR images. HUM provided biospecimens and clinical data. DAL, JA, CT, AM, GR, KW, ET, MK, OAA, and TJM provided clinical data. ECE supervised the overall study. MCW, BJB, FMF, IM, and ECE wrote the initial manuscript. All authors saw, had the opportunity to comment on, and approved the final draft.

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Correspondence to Irini Manoli or Elizabeth C. Engle.

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The Institutional Review Boards at Boston Children’s Hospital (Boston, MA) and National Human Genome Research Institute, National Institutes of Health (Bethesda, MD) approved the study. Individual-level data were de-identified. Sharing of medical record information between collaborating sites was covered by an inter-institute collaborative reliance agreement. Studies were performed in compliance with US 45.CFR.46 and the Declaration of Helsinki.

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Whitman, M.C., Barry, B.J., Robson, C.D. et al. TUBB3 Arg262His causes a recognizable syndrome including CFEOM3, facial palsy, joint contractures, and early-onset peripheral neuropathy. Hum Genet 140, 1709–1731 (2021). https://doi.org/10.1007/s00439-021-02379-9

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