Investigation of genotype‐phenotype correlation of TGFBI mutations reveals c.1868G>A; p.(Gly623Asp) is associated with a variable clinical phenotype, including epithelial basement membrane dystrophy

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PurposeAutosomal dominant mutations in TGFBI cause a range of clinically distinct corneal dystrophies. We investigated the TGFBI mutation spectrum in our cohort and correlated genotype with phenotype.MethodsTGFBI exons 4, 11, 12, 13, 14 and 16 were Sanger sequenced in 59 unrelated probands attending Moorfields Eye Hospital with a diagnosis of a potential TGBFI‐associated corneal dystrophy.ResultsThe majority of individuals, 86%, carried a mutation at one of the two known hotspot residues for TGFBI‐associated corneal dystrophies: Arg‐124 and Arg‐555. Mutations affecting either of these residues demonstrated genotype‐phenotype correlation. A c.1868G>A; p.(Gly623Asp) mutation was identified in five unrelated probands; one with a clinical diagnosis of lattice corneal dystrophy, two with a Bowman's layer dystrophy (Reis‐Bϋcklers or Thiel‐Behnke corneal dystrophy) and two with epithelial basement membrane dystrophy (EBMD). The clinical variability associated with this mutation indicates that other genetic or environmental factors can influence phenotypic expression.ConclusionsThis is the first time the c.1868G>A; p.(Gly623Asp) mutation has been associated with EBMD, although other mutations in TGFBI have previously been identified in a small number of EBMD patients. These results demonstrate that the c.1868G>A; p.(Gly623Asp) mutation is responsible for a significant proportion of the disease burden for TGFBI‐associated corneal dystrophies in the UK and highlights the need for patients with EBMD to be screened for mutations in TGFBI.