Identification of two novel mutations in CDHR1 in consanguineous Spanish families with autosomal recessive retinal dystrophy

Abstract

Purpose: To clinically describe and identify the molecular etiology of autosomal recessive retinal dystrophy in two consanguineous Spanish families.

Methods: Following extensive ophthalmic clinical evaluation, 10 individuals from these pedigrees were genotyped using genome-wide SNP arrays. In addition, whole exome sequencing was performed on the DNA from an affected proband of one family. DNA sequencing by the Sanger method was also used for candidate gene screening.

Results: Affected members of the two families exhibited reduced visual acuity, photophobia, defective colour vision, reduced or absent electroretinogram response, macular atrophy, and pigmentary deposits in the peripheral retina. Exome sequencing combined with autozygosity mapping identified a novel homozygous missense mutation (c.1720C>G, p.P574A) in CDHR1. A second novel homozygous single base transition (c.1485+2T>C) affecting one of the two invariant nucleotides of the canonical 5’ splice site of intron 13 in CDHR1 was also detected in the second family by Sanger sequencing. Both nucleotide changes co-segregated with the disease and were not detected among cohorts of unrelated control individuals.

Conclusions: We provide further insight into the clinical and molecular portrait attributed to CDHR1 by reporting two novel homozygous mutations: a splice site change and the sole pathogenic missense change identified to date in this gene.