p.P347Q Rhodopsin Mutation is a Recurrent Founder Allele in Brazilian Individuals with Autosomal Dominant Retinitis Pigmentosa

AUTHORS : Porto, Fernanda B.1, 2; Jones, Evan M4; Sena, Isadora F.3; Sampaio, Shirley A M1; Souza, Milena C.3; Soens, Zachry4; Li, Yumei 4; Simões, Renata3; Chen, Rui4
INSTITUTIONS : 1. INRET - Clínica e Centro de Pesquisa, Belo Horizonte, Minas Gerais, Brazil. 
2. Departamento de Retina e Vítreo, Centro Oftalmológico de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil. 
3. Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Belo Horizonte, Minas Gerais, Brazil. 
4. Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, United States. 

PURPOSE: The p.P347Q RHO mutation is responsible for almost 30% of the autosomal dominant Retinitis Pigmentosa (adRP) in Minas Gerais (MG) – Brazil. The purpose of this study was to describe: the segregation of the p.P347Q RHO mutation in 6 unrelated families from the small isolated city of Tabuleiro-MG; the haplotype reconstruction; and the clinical characteristics of the p.P347Q allele.

METHODS: Visual acuity, retinography, autofluorescense and OCT were performed on 23 patients, and full-field ERG on 6 patients. Blood samples were collected on 23 patients (17 affected and 6 non-affected, ranging from 2 to 61 years old). Three probands were sequenced using a targeted capture panel including 224 known retinal disease genes. Next-generation sequencing (NGS) data was then aligned, processed and filtered against control datasets using an in-house custom pipeline. Identification of p.P347Q from NGS data in each of the unrelated probands was validated through Sanger sequencing. DNA samples of the probands’ parents and additional unrelated individuals linked to Tabuleiro were then collected and Sanger sequenced for the presence of p.P347Q. Informative captured SNPs were used to infer haplotypes across each of these individuals.

RESULTS: A C to A transversion at position 1040 (p.P347Q) of the cDNA has been identified in all 12 RP individuals currently sequenced for the variant. All individuals with this mutation had early-onset night blindness and substantial visual field losses as teenagers. All patients who underwent full field ERG testing demonstrated non-recordable ERGs. Autofluorescence retinography showed maculopathy and a hipoautofluorescent ring around the optic disc in all patients. Lastly, on the basis of conserved haplotypes linked to this pathogenic variant, we propose that p.P347Q spread through a cohort of geographically isolated families by a preceding founder effect.

CONCLUSIONS: The p.P347Q allele represents a founder mutation causing a rapidly progressive form of adRP in our distinct population. The identification of this founder effect and subsequent mutation may greatly simplify the molecular diagnosis of relevant disease in this population with important implications for the speed and cost-efficiency of diagnostic screening and prognostic counseling.