Congenital Cataract Locus in a Seven Generation Family

Abstract

Purpose: Congenital cataract (CC) appears in the first year of life and can be a simple ocular trait or be part of a multi-system disorder. Hereditary cataracts account for up to 25% of congenital cataracts, and multiple different modes of inheritance have been observed. The purpose of this study was to map a CC locus in a 7 generation Ashkenazi Jewish family and evaluate candidate genes in the region. The family exhibits additional phenotypes including microphthalmia, glaucoma, CC+glaucoma, CC+microphthalmia, and there is evidence of consanguinity.

Methods: This IRB-approved study obtained informed consent from 16 members in three generations of the CC family. Participants were examined at the New York Eye and Ear Infirmary. A genome-wide SNP-based linkage analysis was performed using Illumina's Human Omni-Quad BeadChip and whole exome sequencing (Illumina) provided information on a subset of the family. Assuming complete penetrance, the power to detect linkage was determined by simulation using FastSLINK. Multipoint parametric linkage analysis was performed using MERLIN on a subset of ~10,000 inheritance-informative SNPs with intermarker distances of ~250 kb.

Results: Multipoint parametric linkage analysis was carried out assuming both autosomal dominant and recessive modes of inheritance. The autosomal recessive model indicated significant linkage on chromosome 22 from 16.918 to 22.437 Mb (Chr 22q11.21) with a maximum LOD score of 3.61.

Conclusions: This CC locus maps to chromosome 22 with statistically defined boundaries excluding CRYBB2 and CRYBB3, but haplotyping will be needed to tell whether hard recombination break points exclude them. The coding sequence of these known CC genes showed no missense or nonsense mutations, but one silent mutation (not near a splice site) raises the possibility of alternative splicing. The sequence of additional genes inside of the interval will also need to be examined.

Keywords: 539 genetics • 445 cataract • 581 linkage analysis