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R. W. Yee, X. Zhao, S. Subramanyam, H. Nakamura, S. Yoshikawa, E. L. Stock, T. E. Gillette, D. E. Eifrig, Jr.; Spontaneous and Inheritable R555Q Mutation in TGFBI/BIGH3 in Two Unrelated Families Exhibiting Reis-Bücklers Corneal Dystrophy Phenotype. Invest. Ophthalmol. Vis. Sci. 2007;48(13):5858.
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To study two case reports of sporadic Reis-Bücklers corneal dystrophy (RBCD) and determine if the mutation is inheritable.
Twelve patients were recruited from two unrelated families including two affected individuals from family A and one affected from family B. Slit-lamp exam was performed for each patient to determine disease status. Histological analysis of cornea specimens was used to identify pathogenic corneal opacities in two affected patients from family A. DNA was isolated from the blood samples and used to screen for TGFBI/BIGH3 gene mutations. Sixteen polymorphic DNA markers were used to confirm maternity and paternity of affected individuals.
Both families were confirmed to be unrelated. The age of onset of symptoms was less than 2 years for all three affected patients. The clinical diagnosis was made by cornea subspecialists as RBCD by age 6 for the probands and age 3 for the son of proband A. Signs and symptoms included recurrent painful corneal erosions, excessive tearing, and photophobia. Slip-lamp exam revealed typical corneal findings of epithelial haze with diffuse, irregular, geographic opacities. Histopathology showed subepithelial plaques, increased Masson staining of anterior stroma deposits, and irregular Bowman’s layer. No abnormalities were found in the unaffected family members. Molecular analysis of the TGFBI/BIGH3 gene revealed a R555Q mutation in the two probands but not in their parents. Parental test confirmed they are the biological parents of the probands. Therefore, the R555Q mutation detected in these patients occurred spontaneously. The son of the proband A was also affected. Since his mother is normal, he apparently inherited his disease allele from his father.
The R555Q mutation occurred spontaneously and independently in the two unrelated RBCD families. This is the first reported spontaneous mutation at this "hotspot" of TGFBI/BIGH3 to our knowledge. Furthermore, this spontaneous mutation is confirmed to be transmitted to the next generation in one of the families. This study strongly supports the notion that genetic diagnosis is an important tool for diagnosis of RBCD and other corneal dystrophies. A spontaneous mutation should alert clinicians of the existence of genetic alterations for their patients without family history of the disease.
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