A rare variant in ZBED1, a gene from the pseudoautosomal region of the X and Y chromosomes, is a likely cause of dominant retinitis pigmentosa in several large families.

Abstract

Purpose : To identify the cause of autosomal dominant retinitis pigmentosa (adRP) in a cohort of families without mutations in known adRP genes and consequently to characterize a novel, dominant-acting mutation in ZBED1, a gene in the pseudoautosomal region 1 (PAR1) of the X and Y chromosomes.

Methods : Families from the University of Texas and the Ocular Genomics Institute (OGI) cohorts were screened using whole-exome NGS. Following identification of a novel ZBED1 variant in two families, UTAD076 and UTAD1013, a second cohort from the Ocular Genomics Institute (OGI) at Harvard was screened for the variant. Genealogies were established by interviews of family members; additional samples were collected and sequenced. Haplotypes segregating with the mutation were determined using STR and SNV polymorphisms and LOD scores were calculated in two large families from the University of Texas. Blood samples were obtained from an affected/unaffected sib pair and were used to create iPSCs. Whole genome sequencing was performed in both families to rule out additional, co-segregating pathogenic variants.

Results : A novel variant in ZBED1 (c.754T>A, p.Tyr252Asn) was the only segregating, potentially pathogenic, coding variant identified by exome sequencing in two large adRP families. We subsequently identified an additional two patients in the OGI cohort carrying the same heterozygous variant. One patient overlapped with the UTAD1013 family but the other could not be definitively placed in either family. Using the variant as a marker, LOD scores of 3.6 (UTAD1013) and 4.5 (UTAD076) were calculated. The location of the gene in the pseudoautosomal region confounds haplotype analysis, but genealogies suggest an Irish founder.

Conclusions : A novel, dominant-acting gene mutation in a pseudoautosomal gene is the likely cause of retinitis pigmentosa in two large Irish-American families. The phenotype in both families is similar, with relatively late onset in females and earlier onset in males. Genes in the PAR1 escape X-inactivation but still have lower total expression in females. The ZBED1 gene is thought to function as a transcription factor and is ubiquitously expressed. In retina, ZBED1 is expressed in both rod and cone photoreceptors with even higher expression in bipolar and amacrine cells.

This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.