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Clinical heterogeneity in retinitis pigmentosa caused by variants in RP1 and RLBP1 in five extended consanguineous pedigrees.

ABSTRACT: Purpose:The aim of this study is to identify disease-causing variants in five consanguineous Jordanian families with a history of autosomal recessive retinitis pigmentosa (RP), and to investigate the clinical variability across the affected individuals. Methods:Exome sequencing (ES) and ophthalmic examinations were performed to classify the underlying RP-causative variants and their pathogenic consequences. The candidate variants in the affected and unaffected family members underwent segregation analyses with Sanger sequencing. Results:We described four variants in the RP1 and RLBP1 genes as disease-causing across the five families, including novel (c.398delC; p.Pro133GlnfsTer126) and recurrent (c.79delA; p.Thr27ProfsTer26) variants in RLBP1 and two previously reported variants in RP1 ((c.1126C>T; p.Arg376Ter) and (c.607G>A; p.Gly203Arg)). The consequent clinical manifestations were thoroughly investigated using a battery of ophthalmic tests, including electroretinography (ERG), optical coherence tomography (OCT), visual acuity (VA), and fundus examination. The phenotypes indicated clinical heterogeneity, typical RP for variants in RP1, and retinitis punctata albescens (RPA) for variants in RLBP1. Conclusions:This study extends the pathogenic variant spectrum for the RP1 and RLBP1 genes. The study also revealed the consequent clinical progression, severity, and presentation of RP. Furthermore, we confirm that ES is an efficient molecular diagnostic approach for RP.

SUBMITTER: Al-Bdour M

PROVIDER: S-EPMC7305691 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Clinical heterogeneity in retinitis pigmentosa caused by variants in <i>RP1</i> and <i>RLBP1</i> in five extended consanguineous pedigrees.

Al-Bdour Muawyah M Pauleck Svenja S Dardas Zain Z Barham Raghda R Ali Dema D Amr Sami S Mustafa Lina L Abu-Ameerh Mohammed M Maswadi Ranad R Azab Belal B Awidi Abdalla A

Molecular vision 20200619

<h4>Purpose</h4>The aim of this study is to identify disease-causing variants in five consanguineous Jordanian families with a history of autosomal recessive retinitis pigmentosa (RP), and to investigate the clinical variability across the affected individuals.<h4>Methods</h4>Exome sequencing (ES) and ophthalmic examinations were performed to classify the underlying RP-causative variants and their pathogenic consequences. The candidate variants in the affected and unaffected family members under ...[more]

PMID: 32587456

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Project description:PURPOSE: Retinitis pigmentosa (RP) is the most common form of inherited blindness, caused by progressive degeneration of photoreceptor cells in the retina, and affects approximately 1 in 3,000 people. Over the past decade, significant progress has been made in gene therapy for RP and related diseases, making genetic characterization increasingly important. Recently, high-throughput technologies have provided an option for reasonably fast, cost-effective genetic characterization of autosomal recessive RP (arRP). The current study used a single nucleotide polymorphism (SNP) genotyping method to exclude up to 28 possible disease-causing genes in 31 non-consanguineous Australian families affected by arRP. METHODS: DNA samples were collected from 59 individuals affected with arRP and 74 unaffected family members from 31 Australian families. Five to six SNPs were genotyped for 28 genes known to cause arRP or the related disease Leber congenital amaurosis (LCA). Cosegregation analyses were used to exclude possible causative genes from each of the 31 families. Bidirectional sequencing was used to identify disease-causing mutations in prioritized genes that were not excluded with cosegregation analyses. RESULTS: Two families were excluded from analysis due to identification of false paternity. An average of 28.9% of genes were excluded per family when only one affected individual was available, in contrast to an average of 71.4% or 89.8% of genes when either two, or three or more affected individuals were analyzed, respectively. A statistically significant relationship between the proportion of genes excluded and the number of affected individuals analyzed was identified using a multivariate regression model (p<0.0001). Subsequent DNA sequencing resulted in identification of the likely disease-causing gene as CRB1 in one family (c.2548 G>A) and USH2A in two families (c.2276 G>T). CONCLUSIONS: This study has shown that SNP genotyping cosegregation analysis can be successfully used to refine and expedite the genetic characterization of arRP in a non-consanguineous population; however, this method is effective only when DNA samples are available from more than one affected individual.

Dataset Information

Clinical heterogeneity in retinitis pigmentosa caused by variants in RP1 and RLBP1 in five extended consanguineous pedigrees.

Publications

Clinical heterogeneity in retinitis pigmentosa caused by variants in <i>RP1</i> and <i>RLBP1</i> in five extended consanguineous pedigrees.

Similar Datasets

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