Longitudinal course and genotype-phenotype correlation in patients and carriers with heterozygous mutations in hBEST1 (bestrophin).

Thirteen patients and seven possible carriers were characterised by mutation analysis with SSCPA and direct sequencing, clinical examination and fundus autofluorescence (AF). Electrophysiology (EOG and mfERG) and optical coherence tomography (OCT) were additionally performed whenever possible.

We identified seven different heterozygous mutations in ten unrelated families with Best disease. I296del was the most frequent mutation. Five of nine individuals with I295del and two of three with N99K were asymptomatic carriers. One patient with I295del mutation had funduscopically unilateral Best disease. In three children (all with I295del), EOG initially showed a clearly present light peak that deteriorated during 5 years of follow-up in two of them. Increased AF corresponded well to funduscopically visible lesions. During 3–6 years of follow-up, the lesion area did not change significantly, but there were obvious changes in the inner structure of the lesion.

In the present series I295del, the most frequent mutation in our study, and N99K showed reduced penetrance. EOG was normal in young patients even if prime signs were visible. The lesion area did not depend on the mutation and did not correlate with VA. Lower VA was associated with a more irregular AF pattern due to scarring or haemorrhage. Our results indicate a disease causing effect that is cumulative over time.