Recessive congenital total cataract with microcornea and heterozygote carrier signs caused by a novel missense CRYAA mutation (R54C)

PURPOSE: To determine the genetic basis for congenital total white cataract with microcornea in three affected siblings. DESIGN: Prospective interventional case series. METHODS: Clinical ophthalmic examination, venous blood sampling for linkage analyses, and diagnostic testing of identified candidate gene(s). RESULTS: Three siblings had congenital total white cataract with microcornea; the parents and seven other siblings were asymptomatic. Linkage analysis mapped the phenotype to Hsa 21q22.3, the region of the gene for the alpha-A component of alpha-crystallin (CRYAA), with a logarithm of odds (LOD) score of 2.5. Diagnostic CRYAA sequencing revealed a novel homozygous non-sense mutation (R54C) in the three affected individuals only. One other sibling and the two parents were heterozygotes; these individuals had punctuate lenticular opacities evident by careful slit-lamp biomicroscopy which were not present in the noncarriers, all of whom had unremarkable ophthalmic examinations. CONCLUSION: R54C is the second reported recessive CRYAA mutation associated with congenital cataract and the first with described morphology: punctuate lenticular opacities in carriers and congenital total white cataract with microcornea in homozygotes. The microcornea may have been caused by an inductive effect on the developing cornea from the abnormal lens and/or reduced CRYAA molecular chaperoning of the cornea.