Identification of a novel mutation in the CDHR1 gene in a family with recessive retinal degeneration

Abstract

Objectives: To describe the clinical phenotype and identify the molecular basis of disease in a consanguineous family of Palestinian origin with autosomal recessive retinal degeneration.

Methods: Eight family members were evaluated with visual acuity and perimetry tests, color fundus photographs, full-field electroretinography, and optical coherence tomography. Cone photoreceptors surrounding the fovea were imaged in 2 members, using adaptive optics scanning laser ophthalmoscopy. Exome was captured using probes and sequenced. Readings were mapped to reference hg19. Variant calls and annotations were performed, using published protocols. Confirmation of variants and segregation analysis was performed using dideoxy sequencing.

Results: Analysis detected 24 037 single-nucleotide variants in one affected family member, of which 3622 were rare and potentially damaging to encoded proteins. Further analysis revealed a novel homozygous nonsense change, c.1381 C>T, p.Gln461X in exon 13 of the CDHR1 gene, which segregated with retinal degeneration in this family. Affected members had night blindness beginning during adolescence with progressive visual acuity and field loss and unmeasurable electroretinographic responses, as well as macular outer retinal loss, although residual cones with increased cone spacing were observed in the youngest individual.

Conclusions: Exome analysis revealed a novel CDHR1 nonsense mutation segregating with progressive retinal degeneration causing severe central vision loss by the fourth decade of life. High-resolution retinal imaging revealed outer retinal changes suggesting that CDHR1 is important for normal photoreceptor structure and survival.

Clinical relevance: Exome sequencing is a powerful technique that may identify causative genetic variants in families with autosomal recessive retinal degeneration.

Figure 1

Pedigree and electropherogram of the family studied. A, Pedigree with autosomal recessive retinal degeneration segregates with the c.1381 C>T CDHR1 mutation. Squares indicate males; circles, females; shaded symbols, retinal degeneration; double lines, consanguinity; and slash marks, individuals who had died. B, Electropherograms with the sequence of the CDHR1 gene encompassing the c.1381 C/T region showing the homozygous c.1381 C>T change identified in the affected siblings, the sequence of an unaffected family member with the c.1381 C>T change in the heterozygous state, and the wild-type sequence at the c.1381 nucleotide of the CDHR1 gene.

Figure 2

Clinical features in the affected family members. A, D, G, and J, Color fundus photographs. B, E, H, and K, Goldmann perimetry. C, F, I, and L, Spectral-domain optical coherence tomographic images through fixation, except in family member IV-1, where black lines indicate vertical scan location. Homozygotes show outer retinal loss with hyperreflective lesions in the outer nuclear layer (black arrows). The asterisk indicates a region of mild retinal pigment epithelial (RPE) depigmentation; red arrows, disrupted reflectivity of the outer segment–RPE junction and hyperreflective lesions external to the external limiting membrane and inner-segment ellipsoid band. OD indicates right eye; OS, left eye.

Figure 3

High-resolution foveal images. A, Color fundus photograph for family member III-1. B, Color fundus photograph for IV-4. C, Adaptive optics scanning laser ophthalmoscopy (AOSLO) image for III-1. D, Spectral-domain optical coherence tomography (OCT) for III-1. E, AOSLO image for IV-4. F, Spectral-domain OCT for IV-4. In family member III-1, cones are not seen in some regions (white asterisk, red arrow). In IV-4, the thin outer nuclear layer shows hyperreflective lesions and cone spacing is increased. The asterisks indicate a region of mild retinal pigment epithelial (RPE) depigmentation; circled numbers, standard deviations from the normal mean cone spacing; red arrows, subtle disruptions in the reflectivity of the outer segment–RPE junction; and black arrows, hyperreflective lesions in the outer nuclear layer. A and B, Bars indicate the spectral-domain OCT scan location. C and E, Scale bars represent 1°.

Figure 4

International Society for Clinical Electrophysiology of Vision standard full-field electroretinography (ERG) in the family members studied. Rod- and cone-mediated ERG responses were severely reduced in the affected members (IV-1, IV-3, and IV-4) but were within 2 SDs of the normal mean in the heterozygous carrier (III-1).OS indicates left eye; VA, visual acuity.