Genetic Analysis of Corneal Dystrophies

Corneal disease is a major cause of global blindness accounting for around 2% of severe visual impairment in the UK. Corneal dystrophies are a group of rare, bilateral conditions with a genetic basis. In conjunction with the British Ophthalmic Surveillance Unit (BOSU), a national incidence for new cases of corneal dystrophy in patients aged below 40 years was identified. 73 cases were reported to BOSU with 27 cases (42%) returned by questionnaire. There was a positive family history in 48% of cases. A minimum UK incidence for new cases per annum of 6.7 cases per 10 000 000 population was calculated. To investigate the link between Congenital Hereditary Endothelial Dystrophy (CHED), Harboyan syndrome and Fuchs Endothelial Corneal Dystrophy (FECD), a longitudinal observational study was performed. CHED and Harboyan syndrome (CHED with sensorineural hearing loss) are both caused by biallelic mutations in SLC4A11. All four of the CHED patients examined had varying degrees of hearing loss at high frequencies, suggesting that CHED and Harboyan syndrome are the same condition at different developmental stages. In addition, two of the four parents of CHED patients examined had guttata, suggesting that the parents are at risk of developing FECD. FECD is a common, complex corneal endothelial disease. The relative contributions of the TCF4 SNP rs613872, the intronic TCF4 CTG18.1 trinucleotide expansion and LOXHD1 variants in a UK Caucasian FECD cohort ethnically-matched controls were compared. The results of segregation of the CTG18.1 expansion and whole exome sequencing in three local FECD families indicated that the CTG18.1 expansion was causative for the FECD in two of the three families. This indicated that the TCF4 expansion is a major contributor to the pathogenesis of FECD. Whole exome sequencing in the third family revealed some good gene candidates, which were considered for further screening in the FECD cohort