An Autosomal Dominant TUBB3 Mutation Associated With Congenital Fibrosis of the Extraocular Muscles Type 3 in an Iranian Family.

INTRODUCTION: Congenital fibrosis of the extraocular muscles type 3 (CFEOM3) is a congenital cranial dysinnervation disorder (CCDD) marked by variable ophthalmoplegia and ptosis with considerable phenotypic heterogeneity. We report a large multigenerational Iranian family with autosomal dominant CFEOM3.

METHODS: Affected individuals underwent a comprehensive ophthalmologic evaluation. Whole-exome sequencing (WES) in the proband, followed by Sanger sequencing in 10 affected and 4 unaffected relatives, identified a heterozygous missense variant, c.784C>T (p.Arg262Cys), in exon 4 of TUBB3 (16q24.3), which cosegregated with the disease phenotype.

RESULTS: Cranial magnetic resonance imaging in 2 affected individuals revealed asymmetric basal ganglia morphology, predominantly affecting the caudate nuclei and putamen. At the level of the anterior commissure, the bilateral CFEOM3 patient lacked a visible commissure, whereas the unilateral patient exhibited a thin but identifiable structure. Midline sagittal imaging demonstrated corpus callosum dysgenesis in both individuals, with slightly greater involvement of the corpus callosum body in the unilateral case, though this difference was not radiologically significant. Despite differences in ocular phenotype, overall cerebral involvement was largely comparable.

CONCLUSION: These findings confirm the pathogenic role of the TUBB3 p.Arg262Cys variant in CFEOM3A and extend the spectrum of ophthalmologic and neuroimaging abnormalities within an extended family. The results highlight the complex genotype-phenotype relationships in TUBB3-related disease and underscore the importance of integrated clinical and molecular evaluation for precise diagnosis.

HIGHLIGHTS: TUBB3 R262C segregates with CFEOM3A in a large Iranian family.Brain MRI shows asymmetric basal ganglia and corpus callosum dysgenesis.The anterior commissure is absent in bilateral cases, thin but visible in unilateral cases.Ophthalmoplegia severity varies among affected individuals.Our findings expand the genotype-phenotype spectrum of TUBB3-related CFEOM3A.

PLAIN LANGUAGE SUMMARY: Some people are born with a condition called congenital fibrosis of the extraocular muscles type 3 (CFEOM3), which limits eye movement and may cause drooping eyelids. The severity of eye problems can differ even among family members. We studied a large Iranian family with several members affected by CFEOM3A. Medical exams, eye tests, brain imaging, and DNA analysis were performed. We identified a specific change in the TUBB3 gene, c.784C>T, present in all affected members but absent in healthy relatives. This change likely disrupts normal eye and nerve development, explaining the observed eye problems. Brain imaging showed that this gene change can also alter brain structures, including the basal ganglia and connections between the brain's two hemispheres. Family members with more severe eye problems had more noticeable brain changes, helping explain the variability in symptoms. These findings improve understanding of how a single genetic change can affect both eye and brain development. This knowledge can aid diagnosis, guide families, and may eventually help develop better strategies to manage congenital eye movement disorders.