Instability of TCF4 triplet repeat expansion with parent– child transmission in Fuchs’ endothelial corneal dystrophy

PURPOSE. Fuchs’ endothelial corneal dystrophy (FECD) caused by the CTG triplet repeat expansion in the TCF4 gene (CTG18.1 locus) is the most common repeat expansion disorder. Intergenerational instability of expanded repeats and clinical anticipation are hallmarks of other repeat expansion disorders. In this study, we examine stability of triplet repeat allele length and FECD disease severity in parent–child transmission of the expanded CTG18.1 allele. METHODS. We studied 44 parent–child transmissions of the mutant expanded CTG18.1 allele from 26 FECD families. The CTG18.1 polymorphism was genotyped using short tandem repeat analysis, triplet repeat primed PCR assay, and Southern blot analysis. FECD severity was assessed using modified Krachmer grading (KG) system. Triplet repeat length of mutant allele and KG severity were compared between generations. RESULTS. Instability of the expanded allele was seen in 14 of 44 (31.8%) parent–child transmissions, and the likelihood of an unstable event increased with the size of the parental allele (P = 5:9 ☓ 10 ³ ). A tendency for contraction was seen in transmission of large alleles (repeat length > 120), whereas intermediate alleles (repeat length between 77 and 120) had predilection for further expansion (P = 1:3 ☓ 10 ^-3 ). Although we noted increased KG severity in the offspring in three pairs, none of these transmissions were associated with allele instability. CONCLUSIONS. We observed instability of the TCF4 triplet repeat expansion in nearly a third of parent–child transmissions. Large mutant CTG18.1 alleles are prone to contraction, whereas intermediate mutant alleles tend to expand when unstably transmitted. Intergenerational instability of TCF4 repeat expansion has implications on FECD disease inheritance.