Reduced penetrance in familial Avellino corneal dystrophy associated with TGFBI mutations

PURPOSE: To characterize the clinical phenotype, histopathological features, and molecular genetic basis of an Avellino corneal dystrophy (ACD) in a Chinese family. METHODS: A complete ophthalmologic examination was performed in 21 individuals (6 affected and 15 unaffected) of the four-generation family. DNA was obtained from peripheral blood leukocytes of each participant. Genetic analysis included TGFBI polymerase chain reaction (PCR) amplification and automated nucleotidic sequenceing of all 17 exons of genomic DNA. Histological analysis of corneal tissue from the proband was performed after a penetrating keratoplasty. One hundred Chinese controls were scanned for the presence of the R124H mutation by amplifying TGFBI exon 4 and then by direct sequencing of PCR products. RESULTS: The proband of the pedigree had phenotypic features consistent with diagnosis of ACD. He was homozygous for the same R124H mutation in TGFBI as previously reported in Japan and European countries. In addition, 4 affected and 7 unaffected individuals carried the same variation in the heterozygous state were identified. None of the 100 control subjects was positive for this mutation. Moreover, a variable expressivity and an apparent non-penetrance were observed in the individuals with heterozygous R124H mutation in our pedigree. After excluding the missed diagnosis or a late onset, it could be interpreted as a reduced penetrance. CONCLUSIONS: We reported a novel ACD family which exhibited a reduced penetrance of phenotype in northern China. This outcome supports that although the R124H mutation is one of the genetic causes of the disease, different genetic and environmental factors may influence the expressivity and the penetrance. Uncovering the mechanism may facilitate us to inhibit the occurrence of the corneal dystrophy caused by the R124H mutation in TGFBI, irrespective of the homozygous and heterozygous mutation.