Whole genome sequencing revealed mutations in two independent genes as the underlying cause of retinal degeneration (RD) in an Ashkenazi Jewish Pedigree

Abstract

Purpose : To clinically characterize the phenotype and identify the underlying cause of RD in 2 affected siblings and an affected cousin in a non-consanguineous 4-generation pedigree.

Methods : Detailed ophthalmic evaluation was performed in 3 affected family members. Whole exomes of 3 affected and 2 unaffected family members were sequenced (WES) using Agilent probes and Illumina HISeq. Similarly, whole genomes of family members were sequenced (WGS) at 30X depth using Illumina HiSeq X10. Sequence reads were aligned using BWA-MEM and variant calling was performed using GATK. Copy number variations (CNVs) were called using Genome STRiP and SpeedSeq software. Variants were filtered to detect rare potentially deleterious variants segregating with disease. Segregation was tested by dideoxy sequencing.

Results : Two affected sisters presented with nyctalopia, epiretinal membrane, minimal retinal pigmentary change, midperipheral visual field loss and rod-greater-than-cone dysfunction beginning in the 3^rd decade in the older sister and 5^th decade in the younger sister; their cousin showed bilateral cystoid macular edema and reduced visual acuity at age 39, but later developed midperipheral scotomas and nyctalopia at age 56. WES did not identify potentially pathogenic variants shared by all 3 affected members. However, a previously reported mutation p. Arg 76* in KIZ was observed in the homozygous state in both affected sisters, but not in the cousin. WGS identified about 4 million variants in each individual, but filtering these did not find potentially disease causing variants shared by all 3 affected members. Further analysis revealed the presence of a 1.5 kb homozygous deletion encoding a region in a retina specific transcript of the C21orf2 in the affected cousin. The sisters with the KIZ mutation carried no copies of the C21orf2 mutation, and the cousin with the C21orf2 mutation carried no copies of the KIZ mutation.

Conclusions : This study revealed two independent homozygous mutations in KIZ and C21orf2 genes associated with autosomal recessive rod-cone dystrophy in a 4 generation pedigree. The results demonstrate the importance of comprehensive genetic analysis in all affected family members, given that more than one gene may be responsible for RD in the same family.

This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.