Severe retinitis pigmentosa phenotype associated with novel CNGB1 variants

Abstract

Purpose: To report a severe phenotype of retinitis pigmentosa associated with novel mutations in CNGB1.

Observations: Six siblings, age range 50-75 years old, were examined using optical coherence tomography and fundus autofluorescene, electroretinogram testing, Goldman visual field testing, and genetic testing using next generation sequencing.In four affected siblings, two novel compound heterozygous variants in CNGB1 were detected: in exon 26 the missense variant c.2603G > A (p.(Gly868Asp)), and in exon 21, the in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.(Cys698_lle701dup)). One sibling was unaffected and carried neither of the variants, while another sibling had mild macular degeneration changes and carried the latter variant in heterozygous status. The affected siblings presented with a phenotype showing markedly constricted visual field, flat scotopic and photopic electroretinogram responses and generalized retinal atrophy.

Conclusions and importance: This is the first report of a 12bp in-frame duplication and a missense variant (in compound heterozygous status) in CNGB1, being associated with a severe form of retinitis pigmentosa featuring extensive peripheral and central retinal degeneration. This study expands the molecular genetic basis of CNGB1-related disease.

Keywords: CNGB1; Novel variant; Retinitis pigmentosa; Rod-cone dystrophy.

© 2020 The Authors.

Figures

Fig. 1

The family pedigree of a 66-year-old male with severe RP associated with a heterozygous missense variant c.2603G > A (p.Gly868Asp) in exon 26 of CNGB1 and a heterozygous in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.Cys698_lle701dup) in exon 21of CNGB1variants.

Fig. 2

Imaging in a 66-year-old male with severe RP associated with a heterozygous missense variant c.2603G > A (p.Gly868Asp) in exon 26 of CNGB1 and a heterozygous in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.Cys698_lle701dup) in exon 21of CNGB1variants. A&B: Color fundus photos of the right and left eye. Both eyes show extensive RPE atrophy, intra-retinal pigment migration, attenuated retinal vessels, and pale optic discs. C&D: AF imaging of the right and left eye showing a small preserved island of about 3 disc diameters with loss of signal outside that island. E&F: OCT horizontal cut through the fovea of the right and left eye showing a small central zone of preserved inner segment ellipsoid (ISe) (the area between the arrows) and loss of the ISe outside that area. . (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)

Fig. 3

Goldman visual field test in of a 66-year-old male with severe RP associated with a heterozygous missense variant c.2603G > A (p.Gly868Asp) in exon 26 of CNGB1 and a heterozygous in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.Cys698_lle701dup) in exon 21of CNGB1variants. Note the severe constriction of the VF down to 10° with size IV object.

Fig. 4

ffERG results in of a 66-year-old male with severe RP associated with a heterozygous missense variant c.2603G > A (p.Gly868Asp) in exon 26 of CNGB1 and a heterozygous in-frame 12-bp duplication c.2093_2104dupGCGACCTCATCT (p.Cys698_lle701dup) in exon 21of CNGB1variants. OD = Right eye. OS = Left eye. N = Normal age matched result.