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Fatemeh Sadat Rashidi1 
, Ehsan Ahmadipour1 , Afagh Alavi2 , Hamed Javadian3 , Parisa Azimi4 , Setareh Shomali5 , Motahhareh Sadeghi6 , Nader Maghsoudi7 , Abbas Bagher8 , Noor Mohamad Ghiasvand *1
, Ehsan Ahmadipour1 , Afagh Alavi2 , Hamed Javadian3 , Parisa Azimi4 , Setareh Shomali5 , Motahhareh Sadeghi6 , Nader Maghsoudi7 , Abbas Bagher8 , Noor Mohamad Ghiasvand *1
1- Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
2- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
3- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Ira
4- Department of Neurosurgery, Clinical Research Development Unit of Shahid Madani Hospital, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
5- Department of ophthalmology, Sari Branch, Islamic Azad University of Medical Science, Sari, Iran.
6- Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.
7- Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran. & Department of Biology, Queens College and Graduate Center of the City University of New York, Flushing, NY, USA. & Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
8- Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
2- Genetics Research Center, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran.
3- Functional Neurosurgery Research Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical Sciences, Tehran, Ira
4- Department of Neurosurgery, Clinical Research Development Unit of Shahid Madani Hospital, School of Medicine, Alborz University of Medical Sciences, Karaj, Iran.
5- Department of ophthalmology, Sari Branch, Islamic Azad University of Medical Science, Sari, Iran.
6- Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran.
7- Neuroscience Research Center, Institute of Neuroscience and Cognition, Shahid Beheshti University of Medical Sciences, Tehran, Iran. & Department of Biology, Queens College and Graduate Center of the City University of New York, Flushing, NY, USA. & Neurobiology Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
8- Farabi Eye Hospital, Tehran University of Medical Sciences, Tehran, Iran
Abstract:
Congenital fibrosis of the extraocular muscles type 3 (CFEOM3) is a congenital cranial dysinnervation disorder marked by variable ophthalmoplegia and ptosis with considerable phenotypic heterogeneity. We report a large multigenerational Iranian family with autosomal dominant CFEOM3. Affected individuals underwent comprehensive ophthalmologic evaluation. Whole-exome sequencing in the proband, followed by Sanger sequencing in ten affected and four unaffected relatives, identified a heterozygous missense variant, c.784C>T (p.Arg262Cys), in exon 4 of TUBB3 (16q24.3), which co-segregated with the disease phenotype.
Cranial magnetic resonance imaging (MRI) in two 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.
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.
Cranial magnetic resonance imaging (MRI) in two 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.
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.
Type of Study: Original |
Subject:
Behavioral Neuroscience
Received: 2025/12/22 | Accepted: 2025/12/22
Received: 2025/12/22 | Accepted: 2025/12/22
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