Next generation sequencing identified novel heterozygous nonsense mutation in CNGB1 gene associated with retinitis pigmentosa in a Chinese patient

Abstract

Retinitis pigmentosa (RP) is a severe hereditary eye disease characterized by progressive degeneration of photoreceptors and subsequent loss of vision. Retinitis pigmentosa (RP) is a clinically and genetically heterogeneous group of retinal diseases. Germline mutations of CNGB1 is associated with retinitis pigmentosa. We have identified and investigated a 34-year-old Chinese man with markedly have night vision blindness and loss of midperipheral visual field. The proband also lose his far peripheral visual field and also central vision. Proband's retinal pigment deposits visible on fundus examination and primary loss of rod photoreceptor cells followed by secondary loss of cone photoreceptors. Target exome capture based next generation sequencing and Sanger sequencing identified novel nonsense mutation, c.1917G>A and a reported mutation, c.2361C>A, in the CNGB1 gene. Both the nonsense mutations are predicted to lead to the formation of a premature stop codon which finally results into formation of truncated CNGB1 protein product which finally predicted to be disease causing. According to the variant classification guidelines of ACMG, these two variants are categorized as "likely pathogenic" variants. Our findings expand the mutational spectra of CNGB1 and are valuable in the mutation-based pre- and post-natal screening and genetic diagnosis for retinitis pigmentosa.

Keywords: CNGB1gene; Pathology Section; loss of vision; midperipheral visual field; retinitis pigmentosa; rod photoreceptor cells.

Figure 1. Pedigree of the family

The filled symbol indicates the patient (proband), and the half-filled symbols show the carrier parents, who were heterozygous carriers but were unaffected. The arrow points to the proband.

Figure 2. Partial DNA sequences in the CNGB1 by Sanger sequencing of the family [NM_001297]

Upper line: the proband, middle line: the father, bottom line: the mother. Arrows point to the mutations. The proband inherited both c.1917G>A and c.2361C>A mutations. The father carries the c.1917G>A mutation, and the mother carries the c.2361C>A mutation.

Figure 3. Filtering process for pathogenic mutations in all variations obtained by exome sequencing

*Databases used: dbSNP, Hapmap, 1000 Genomes Project and BGI’s in–house database of ∼30000 Chinese people. SNV: single nucleotide variation. Indel: small insertion and deletion.