PURPOSE: Identification of the causal mutations in 28 unrelated families and individuals with hereditary congenital cataract identified from a national Danish register of hereditary eye diseases. Seven families have been published previously, and the data of the remaining 21 families are presented together with an overview of the results in all families. METHODS: A combined screening approach of linkage analysis and sequencing of 17 cataract genes were applied to mutation analyses of total 28 families. RESULTS: The study revealed a disease locus in seven of eight families that were amenable to linkage analysis. All loci represented known genes, and subsequent sequencing identified the mutations. Mutations were found in eight genes, among them crystallins (36%), connexins (22%), and the transcription factors HSF4 and MAF (15%). One family carried a complex CRYBB2 allele of three DNA variants, and a gene conversion is the most likely mutational event causing this variant. Ten families had microcornea cataract, and a mutation was identified in eight of those. Most families displayed mixed phenotypes with nuclear, lamellar, and polar opacities and no apparent genotype-phenotype correlation emerged. CONCLUSIONS: In total, 28 families were analyzed, and mutations were identified in 20 (71%) of them. Despite considerable locus heterogeneity, a high mutation identification rate was achieved by sequencing a limited number of major cataract genes. Provided these results are representative of Western European populations, the applied sequencing strategy seems to be suitable for the exploration of the large group of isolated cataracts with unknown etiology.
Keywords: Adolescent; Adult; Amino Acid Sequence; Base Sequence; Cataract; Child, Preschool; Connexins; Cornea; Crystallins; DNA Mutational Analysis; DNA-Binding Proteins; Denmark; European Continental Ancestry Group; Eye Diseases, Hereditary; Female; Genotype; Humans; Linkage (Genetics); Lod Score; Male; Middle Aged; Molecular Sequence Data; Mutation; Pedigree; Phenotype; Polymerase Chain Reaction; Proto-Oncogene Proteins c-maf; Registries; Sequence Analysis, DNA; Transcription Factors; beta-Crystallin B Chain; gamma-Crystallins