Original articleIdentification of an RP1 Prevalent Founder Mutation and Related Phenotype in Spanish Patients with Early-Onset Autosomal Recessive Retinitis
Section snippets
Patient Recruitment
Patients diagnosed with early-onset RP were recruited from the Fundación Jiménez Díaz Hospital (Madrid, Spain). Diagnostic criteria of early-onset RP included night blindness or peripheral visual loss in the first decade of the life, with poor visual acuity and visual field loss in advanced stages of the disease.
A total of 244 unrelated Spanish families with autosomal recessive or sporadic early-onset RP were selected, because the first symptoms appear in the first decade of life in patients
Materials and Methods
Peripheral blood samples of index cases and their family members were collected in ethylenediaminetetraacetic acid tubes. DNA was extracted from peripheral blood leukocytes with an automated DNA extractor (model BioRobotEZ1; QIAGEN, Hilden, Germany) following the manufacturer's instructions.
Results
Two Spanish families (RP-0056 and RP-1296) were analyzed on a high-resolution SNP array to identify the genetic cause underlying their early-onset arRP. The family RP-0056, comprising 2 affected siblings, showed a high number of homozygous regions (>15) ranging from 1 to 5.6 Mb. In family RP-1296, the 3 affected siblings shared 3 homozygous regions of 1, 1.3, and 7.8 Mb (data not shown). Both families presented a common region: the first and third largest homozygous region located in
Discussion
RP1 is considered a rare causal gene for recessive retinal degeneration.14 This is probably the reason why RP1 is seldom screened in patients with arRP, and no extensive RP1 study for this class of individuals has been reported. We report a single founder mutation; the mutation has been inherited from a common ancestral origin, in the RP1 gene, p.Ser542Stop, which accounts for the 4.5% of the cases and seems to be the most prevalent mutation in our cohort of Spanish patients affected by
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Identification of RP1 as the genetic cause of retinitis pigmentosa in a multi-generational pedigree using Extremely Low-Coverage Whole Genome Sequencing (XLC-WGS)
2023, GeneCitation Excerpt :The XLC-WGS-based analysis is also three-times cheaper than a non-clinical whole-exome sequencing - WES (∼$300 USD/individual). Most notably, XLC-WGS unveiled the rs779334655 variant as a causal variant for a likely recessive form of RP in our family of interest, consistent with previous independent studies (Avila-Fernandez et al., 2012; Ezquerra-Inchausti et al., 2018; Silva et al., 2020) and supported RP1 as the causal variant for the RP phenotype. The data produced by the XLC-WGS was confirmed by Sanger Sequencing, proving its reliability.
Compound dominant-null heterozygosity in a family with RP1-related retinal dystrophy
2022, American Journal of Ophthalmology Case ReportsCitation Excerpt :Further case reports have largely validated the general principles of this classification,2 however, there are several examples of pathogenic variants that fall within the class II cluster that appear to be recessively inherited.19 A notable example is the p.Ser542Ter founder variant which underlies approximately 5% of autosomal recessive retinitis pigmentosa in a Spanish population, with heterozygous members of these families appearing to be clinically normal.20 Further examples include the p.Ser574Asnfs*8 pathogenic variant which has been found to cause disease in a homozygous state only - including in a case of uniparental disomy of chromosome 8 21 - and p.Asp799*19.
Genomic Landscape of Sporadic Retinitis Pigmentosa: Findings from 877 Spanish Cases
2019, OphthalmologyCitation Excerpt :As expected, biallelic pathogenic variants in genes carrying AR-inherited defects were the most frequent, and USH2A and CRB1 are the most commonly mutated genes in our cohort, as previously described in another Spanish cohort,13 explaining up to 28% of our characterized patients. As previously described in another sRP Spanish cohort,13 the most prevalent pathogenic alleles were p.(Cys759Phe) in USH2A, known to be one of the most frequent pathogenic variants worldwide,7,29 and the previously reported Spanish founder variants p.(Arg283*), and p.(Ser542*) in CERKL30 and RP1,19 respectively. Approximately 16% of the cases carried pathogenic variants consistent with a non-AR inheritance.
Advancing precision medicines for ocular disorders: Diagnostic genomics to tailored therapies
2022, Frontiers in Medicine
Manuscript no. 2012-254.
Financial Disclosure(s): This study was supported by the following research grants: FIS PI09/90047, FIS PS09/00459, RD09-0076-00101 (Retics Bionbank), the Centre for Biomedical Network Research on Rare Diseases (CIBERER) Intra/07/704.1 and Intra/09/702.1, and Fundaluce 2011. Additional support was provided by the Swiss National Science Foundation (Grant 310030_138346) and the Gebert-Rüf Foundation (Rare Diseases – New Technologies Grant). AA-F is sponsored by the research grant FIS (Sanitary Research Fund) PS09/00459, and MC is sponsored by the CIBERER.
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Both authors contributed equally to this work.