Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population

Gamundi, María José; Hernán, Imma; Martinez-Gimeno, María; Maseras, Miquel; Garcı́a-Sandoval, Blanca; Ayuso, Carmen; Antiñolo, Guillermo; Baiget, Montserrat; Carballo, Miguel

doi:10.1186/1471-2350-7-35

Cited by 16 publications

(10 citation statements)

References 30 publications

(33 reference statements)

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“…Also, the phenotype of the patients argues in favour of this finding due to the recessive mutations in the RP1 gene cause an early onset RP 24 . Although there was not antecedents of retinal degeneration in the family, we could confirm the frameshift mutation also in a non-affected sibling supporting the existence of the incomplete penetrance previously reported in this gene 25 . Thus, the identification of the genetic defect becomes increasingly relevant, especially when gene-specific therapeutic approaches are becoming more promising according to the results of the ongoing clinical trials 26 .…”

Section: Discussionsupporting

confidence: 83%

Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

Pérez-Carro

Cortón

Sánchez‐Navarro

et al. 2016

Sci Rep

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Retinitis pigmentosa (RP) is a group of inherited progressive retinal dystrophies (RD) characterized by photoreceptor degeneration. RP is highly heterogeneous both clinically and genetically, which complicates the identification of causative genes and mutations. Targeted next-generation sequencing (NGS) has been demonstrated to be an effective strategy for the detection of mutations in RP. In our study, an in-house gene panel comprising 75 known RP genes was used to analyze a cohort of 47 unrelated Spanish families pre-classified as autosomal recessive or isolated RP. Disease-causing mutations were found in 27 out of 47 cases achieving a mutation detection rate of 57.4%. In total, 33 pathogenic mutations were identified, 20 of which were novel mutations (60.6%). Furthermore, not only single nucleotide variations but also copy-number variations, including three large deletions in the USH2A and EYS genes, were identified. Finally seven out of 27 families, displaying mutations in the ABCA4, RP1, RP2 and USH2A genes, could be genetically or clinically reclassified. These results demonstrate the potential of our panel-based NGS strategy in RP diagnosis.

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Section: Discussionsupporting

confidence: 83%

Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

Pérez-Carro

Cortón

Sánchez‐Navarro

et al. 2016

Sci Rep

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“…Including our findings, to date 47 RP1 mutations are known to cause adRP. The prevalence of RP1 mutations, with 5.3% in our cohort is similar to the studies reported from United Kingdom and United States, although the prevalence of RP1 mutations varied from 0 to 10% in different adRP cohorts [Baum et al, 2001; Berson et al, 2001; Bowne et al, 1999; Gamundi et al, 2006; Kawamura et al, 2004; Payne et al, 2000; Pierce et al, 1999; Roberts et al, 2006; Sohocki et al, 2001; Sullivan et al, 2006; Zhang et al 2010; Ziviello et al, 2005]. Different pathogenic mechanisms of RP1 truncating mutations have been proposed based on in vitro and in vivo studies leading to ar or adRP.…”

Section: Mutations In the Rp1 Genesupporting

confidence: 88%

“…So far, 43 disease‐causing mutations in RP1 have been identified of which most were found in the last exon, leading to a premature stop codon and are predicted to form a truncated protein (Table 1). The p.Arg677X has been described as the most commonly reported mutation [Baum et al, 2001; Berson et al, 2001; Bowne et al, 1999; Chiang et al, 2006; Gamundi et al, 2006; Guillonneau et al, 1999; Jacobson et al, 2000; Payne et al, 2000; Pierce et al, 1999; Roberts et al, 2006; Schwartz et al, 2003; Sohocki et al, 2001; Sullivan et al, 1999, 2006; Wang et al, 2005; Xiaoli et al, 2002; Ziviello et al, 2005]. Detailed phenotype–genotype correlation of patients with this mutation revealed incomplete penetrance and high variability of disease expression of adRP, suggesting modifiers to be involved [Jacobson et al, 2000].…”

Section: Mutations In the Rp1 Genementioning

confidence: 99%

RP1 and autosomal dominant rod-cone dystrophy: Novel mutations, a review of published variants, and genotype-phenotype correlation

et al. 2011

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Rod-cone dystrophies (retinitis pigmentosa [RP]) are a clinically and genetically heterogeneous group of inherited retinal disorders characterized by photoreceptor degeneration. RP1 is a major gene underlying autosomal dominant (ad) RP, though prevalence figures vary depending on the origin of the cases from 0-10% of all adRP. Some mutations in RP1 also lead to autosomal recessive (ar) RP. Herein, we review all previously reported and several novel RP1 mutations in relation to the associated phenotype in RP1 patients from a French adRP cohort. Prevalence studies from this cohort show that 5.3% of the cases have RP1 mutations. This is in accordance with other studies reported from United Kingdom and United States. The majority of mutations represent truncating mutations that are located in a hot spot region of the gene. Similarly, we identified in total four novel deletions and nonsense mutations, of which two may represent recurrent mutations in this population. In addition, a novel missense mutation of uncertain pathogenicity was identified. Including our findings to date, 47 RP1 mutations are known to cause adRP. Variable penetrance of the disease was observed in our and other cohorts. Most patients with RP1 mutations show classical signs of RP with relatively preserved central vision and visual field.

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“…The fact that the vast majority of pathogenic mutations in RP1 result in premature stop codons (nonsense and frameshift mutations) indicate that the most probable adRP-causative mutations in validation sample #8 is p.R667* and not p.E1319G, which might be secondary to the disease and simply reflect the high frequency of carriers harboring heterozygous mutant alleles of IRD genes in the general population [ 24 ]. Additionally, the p.R677* mutation has been reported as the most frequently pathogenic RP1 mutation [ 14 , 25 ] with a location consistent with a dominant inheritance pattern [ 12 ].…”

Section: Discussionmentioning

confidence: 99%

Novel RP1 mutations and a recurrent BBS1variant explain the co-existence of two distinct retinal phenotypes in the same pedigree

et al. 2014

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BackgroundMolecular diagnosis of Inherited Retinal Dystrophies (IRD) has long been challenging due to the extensive clinical and genetic heterogeneity present in this group of disorders. Here, we describe the clinical application of an integrated next-generation sequencing approach to determine the underlying genetic defects in a Spanish family with a provisional clinical diagnosis of autosomal recessive Retinitis Pigmentosa (arRP).ResultsExome sequencing of the index patient resulted in the identification of the homozygous BBS1 p.M390R mutation. Sanger sequencing of additional members of the family showed lack of co-segregation of the p.M390R variant in some individuals. Clinical reanalysis indicated co-ocurrence of two different phenotypes in the same family: Bardet-Biedl syndrome in the individual harboring the BBS1 mutation and non-syndromic arRP in extended family members. To identify possible causative mutations underlying arRP, we conducted disease-targeted gene sequencing using a panel of 26 IRD genes. The in-house custom panel was validated using 18 DNA samples known to harbor mutations in relevant genes. All variants were redetected, indicating a high mutation detection rate. This approach allowed the identification of two novel heterozygous null mutations in RP1 (c.4582_4585delATCA; p.I1528Vfs*10 and c.5962dupA; p.I1988Nfs*3) which co-segregated with the disease in arRP patients. Additionally, a mutational screening in 96 patients of our cohort with genetically unresolved IRD revealed the presence of the c.5962dupA mutation in one unrelated family.ConclusionsThe combination of molecular findings for RP1 and BBS1 genes through exome and gene panel sequencing enabled us to explain the co-existence of two different retinal phenotypes in a family. The identification of two novel variants in RP1 suggests that the use of panels containing the prevalent genes of a particular population, together with an optimized data analysis pipeline, is an efficient and cost-effective approach that can be reliably implemented into the routine diagnostic process of diverse inherited retinal disorders. Moreover, the identification of these novel variants in two unrelated families supports the relatively high prevalence of RP1 mutations in Spanish population and the role of private mutations for commonly mutated genes, while extending the mutational spectrum of RP1.Electronic supplementary materialThe online version of this article (doi:10.1186/s12863-014-0143-2) contains supplementary material, which is available to authorized users.

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Three novel and the common Arg677Ter RP1 protein truncating mutations causing autosomal dominant retinitis pigmentosa in a Spanish population

Cited by 16 publications

References 30 publications

Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

Panel-based NGS Reveals Novel Pathogenic Mutations in Autosomal Recessive Retinitis Pigmentosa

RP1 and autosomal dominant rod-cone dystrophy: Novel mutations, a review of published variants, and genotype-phenotype correlation

Novel RP1 mutations and a recurrent BBS1variant explain the co-existence of two distinct retinal phenotypes in the same pedigree

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