GLA Nonsense Mutation (c.485G>A) in a Three-Generation Family with Fabry’s Disease.

Background: GLA nonsense mutations seem to be associated with more severe clinical phenotype. Aims: Main aims were to identify the disease-causing mutation, to screen high risk family members and to predict the severity of clinical phenotype and age of onset based on genotype-phenotype analysis. Methods: Seven family members were clinically assessed and enzyme activity levels were evaluated as well. Genomic DNA was isolated from blood samples and analyzed for GLA gene mutation. Results: The proband, a 34-year-old man, was misdiagnosed for years. At 25 years of age he was diagnosed with Fabry’s disease. He had a less severe phenotype failing to express cardiac, cerebral or renal symptoms. In addition, the patient presented a ventricular septal defect as an incidental finding which has not been reported previously in Fabry’s disease. His maternal uncle had a severe classic form and, in addition, osteonecrosis of femoral head rarely reported as associated findings. All females were heterozygous; 3 of them were asymptomatic and 2 developed milder symptoms, skin and heart predominantly affected. Fabry’s disease was caused by the presence of GLA nonsense mutation c.485G>A. All close relatives of proband had one copy of the mutation. Conclusion: The family nonsense mutation c.485G>A known to predict the classic phenotype showed a wide range of clinical manifestations from severe to asymptomatic forms both in males and females supporting the intrafamilial phenotypic variability for Fabry’s disease.

Oculo-facio-cardio-dental syndrome in three succeeding generations: genotypic data and phenotypic features

Oculo-facio-cardio-dental (OFCD) syndrome is a rare X-linked disorder mainly manifesting in females. Patients show ocular, facial, cardiac, and dental abnormalities. OFCD syndrome is caused by heterozygous mutations in the BCOR gene, located in Xp11.4, encoding the BCL6 co-repressor. We report a Croatian family with four female members (grandmother, mother and monozygotic female twins) diagnosed with OFCD syndrome who carry the novel BCOR mutation c.4438C>T (p.R1480*). They present high intrafamilial phenotypic variability with special regard to cardiac defect and cataract that showed more severe disease expression in successive generations. Clinical and radiographic examination of the mother of the twins revealed a talon cusp involving the permanent maxillary right central incisor. This is the first known report of a talon cusp in OFCD syndrome with a novel mutation in the BCOR gene.