Novel mega-deletion in BFSP1 causing autosomal recessive juvenile cataract in a Pakistani consanguineous family.

Juvenile cataract is characterized by the blurredness in eye lens which develops typically before the age of 18 years. Objective of the study was to delineate the underlying causative genetic defect for autosomal recessive juvenile cataract (ARJC) in an affected consanguineous multiplex, multigenerational Pakistani consanguineous family. Whole-exome sequencing (WES) in an affected family member revealed a homozygous, intragenic 15.40 kb mega-deletion NG_012423.2; g.17485448_17500744del (chr20: 17,485,448-17,500,744-GRCh37/hg19) including three consecutive exons 3, 4, and 5, encompassing two domains of beaded filament structural protein 1 (BFSP1). Sanger sequencing and PCR were performed for all participants of the family which revealed the absence of the exons (3, 4, 5) in affected individuals and their presence in unaffected parents and siblings confirming the segregation of the mutation as autosomal recessive in the family under study. The large deletion potentially forced the junction of exon 2 with exon 6 at mRNA level and resulting in the shift of open reading frame. The mutation was not observed in 200 unrelated in-house controls. Up to our knowledge, this is the first study reporting the largest mega-deletion encompassing 15.40 kb removal (consisting of 99 amino acids) and reveals the significant role of BFSP1 for physiologic lens function and optical properties. Our findings extend the genotypic spectrum of BFSP1-related cataract.