Novel crystallin gamma B mutations in a Kuwaiti family with autosomal dominant congenital cataracts reveal genetic and clinical heterogeneity

摘要

Purpose: To explore the disease locus and causative mutation for autosomal dominant congenital cataracts (ADCC) in a Kuwaiti family. There were seven affected and three unaffected subjects in the family. Methods: Whole-genome linkage analysis was performed using Gene Chip Human Mapping 250 K Arrays to identify regions of linkage. Potential genes within this region were cloned and sequenced to identify the disease-causing mutation. Results: The highest logarithm of odds score (1.5) region 2q34–36.1, spanning the crystallin beta A2 (CRYBA2) gene, showed no sequence changes. Thus, the second highest logarithm of odds score (1.49) region, 2q33–37, spanning the gamma crystalline gene cluster (CRYG), was considered. Sequencing of the CRYGA, B, C, and D genes revealed two novel heterozygous deletions and one trinucleotide polymorphism in the CRYGB gene. These mutations included a heterozygous g.67delG, intron 1 deletion in four of the affected family members with lamellar cataracts and a heterozygous g.167delC, exon 2 deletion inherited from the Egyptian grandmother by her granddaughter, resulting in anterior polar cataracts. Another patient with complete cataracts was a compound heterozygote with both of the above-mentioned mutations. In addition, the novel trinucleotide polymorphism g.20–22 GGTAAA was detected in three of the family members. Conclusions: We report the linkage of ADCC to chromosome 2q33–37, which spans the CRYGB gene. This study is the first to report complex heterogeneous mutations in the CRYGB gene resulting in ADCC with three distinct phenotypes (lamellar, anterior polar, and complete cataracts) in the same family.