Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study

Jin, Zi‐Bing; Mandai, Michiko; Yokota, Toshifumi; Higuchi, Kaori; Ohmori, Katsuyuki; Ohtsuki, F.; Takakura, Shunji; Itabashi, Toshitaka; Wada, Yuko; Akimoto, Masayuki; Ooto, Satoro; Suzuki, Takuya; Hirami, Yasuhiko; Ikeda, Hanako Ohashi; Kawagoe, Naoaki; Oishi, Akio; Ichiyama, Satoshi; Takahashi, Masayo; Yoshimura, Nagahisa; Kosugi, Shinji

doi:10.1136/jmg.2007.056416

Cited by 65 publications

(54 citation statements)

References 34 publications

(27 reference statements)

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“…Epidemiological studies assessing different populations have indicated that half of all mutations in patients with IRD are sporadic or multiplex, and, unfortunately, those cases are the ones most prevalent in the clinic. 19,29 In our cohort of patients with IRD, 90% of probands displayed sporadic or autosomal recessive mutations, which makes molecular diagnosis more challenging. 30 Several groups, including ours, have attempted to challenge the molecular diagnosis of simplex or autosomal recessive IRD 19,31,32 ; however, the detection rates remained lower than 20%.…”

Section: Discussionmentioning

confidence: 99%

“…19,29 In our cohort of patients with IRD, 90% of probands displayed sporadic or autosomal recessive mutations, which makes molecular diagnosis more challenging. 30 Several groups, including ours, have attempted to challenge the molecular diagnosis of simplex or autosomal recessive IRD 19,31,32 ; however, the detection rates remained lower than 20%. In this study, however, our results showed that 50% of patients with sporadic and 71% of patients with recessive IRD were successfully determined to have genetic predispositions, suggesting that targeted exome sequencing is an efficient and applicable approach for the molecular diagnosis of such patients.…”

Section: Discussionmentioning

confidence: 99%

“…Traditional methods of individual gene screening are difficult and unlikely to reveal the full mutation spectrum in the patient population. Tremendous efforts to develop comprehensive screening strategies have been made, including genotyping microarray, 25 denaturing high-performance liquid chromatography, 19 and high-resolution melting analysis. 26 However, issues such as prolonged processing time and an inability to identify novel mutations persist.…”

Section: Discussionmentioning

confidence: 99%

“…Missense variants were assessed with PolyPhen-2 and SIFT, as described previously. 19 The splice-site effect was predicted using the BDGP (http://www.fruitfly.org/ seq_tools/splice.html) and ASSP programs (http://wangcomputing.com/assp/index.html).…”

Section: In-depth Bioinformatics Analysismentioning

confidence: 99%

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Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Huang

et al. 2015

Genetics in Medicine

180

126

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Purpose: Inherited retinal dystrophy (IRD) is a leading cause of blindness worldwide. Because of extreme genetic heterogeneity, the etiology and genotypic spectrum of IRD have not been clearly defined, and there is limited information on genotype-phenotype correlations. The purpose of this study was to elucidate the mutational spectrum and genotype-phenotype correlations of IRD. Methods:We developed a targeted panel of 164 known retinal disease genes, 88 candidate genes, and 32 retina-abundant microRNAs, used for exome sequencing. A total of 179 Chinese families with IRD were recruited. Results:In 99 unrelated patients, a total of 124 mutations in known retinal disease genes were identified, including 79 novel mutations (detection rate, 55.3%). Moreover, novel genotype-phenotype correlations were discovered, and phenotypic trends noted. Three cases are reported, including the identification of AHI1 as a novel candidate gene for nonsyndromic retinitis pigmentosa. Conclusion:This study revealed novel genotype-phenotype correlations, including a novel candidate gene, and identified 124 genetic defects within a cohort with IRD . The identification of novel genotype-phenotype correlations and the spectrum of mutations greatly enhance the current knowledge of IRD phenotypic and genotypic heterogeneity, which will assist both clinical diagnoses and personalized treatments of IRD patients.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: In-depth Bioinformatics Analysismentioning

confidence: 99%

See 2 more Smart Citations

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Huang

et al. 2015

Genetics in Medicine

180

126

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“…for 30 disease genes identified commonly within North American or European patients revealed candidate pathogenic mutations in only 14% of the cohort (8).…”

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confidence: 99%

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Nishiguchi

Tearle

Liu

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

111

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We performed whole genome sequencing in 16 unrelated patients with autosomal recessive retinitis pigmentosa (ARRP), a disease characterized by progressive retinal degeneration and caused by mutations in over 50 genes, in search of pathogenic DNA variants. Eight patients were from North America, whereas eight were Japanese, a population for which ARRP seems to have different genetic drivers. Using a specific workflow, we assessed both the coding and noncoding regions of the human genome, including the evaluation of highly polymorphic SNPs, structural and copy number variations, as well as 69 control genomes sequenced by the same procedures. We detected homozygous or compound heterozygous mutations in 7 genes associated with ARRP (USH2A, RDH12, CNGB1, EYS, PDE6B, DFNB31, and CERKL) in eight patients, three Japanese and five Americans. Fourteen of the 16 mutant alleles identified were previously unknown. Among these, there was a 2.3-kb deletion in USH2A and an inverted duplication of ∼446 kb in EYS, which would have likely escaped conventional screening techniques or exome sequencing. Moreover, in another Japanese patient, we identified a homozygous frameshift (p.L206fs), absent in more than 2,500 chromosomes from ethnically matched controls, in the ciliary gene NEK2, encoding a serine/threonineprotein kinase. Inactivation of this gene in zebrafish induced retinal photoreceptor defects that were rescued by human NEK2 mRNA. In addition to identifying a previously undescribed ARRP gene, our study highlights the importance of rare structural DNA variations in Mendelian diseases and advocates the need for screening approaches that transcend the analysis of the coding sequences of the human genome. medical genetics | ophthalmology | ciliopathy | retinal blindness

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Mechanisms of blindness: Animal models provide insight into distinct CRX‐associated retinopathies

Tran

Chen

2014

Developmental Dynamics

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The homeodomain transcription factor CRX is a crucial regulator of mammalian photoreceptor gene expression. Mutations in the human CRX gene are associated with dominant inherited retinopathies Retinitis Pigmentosa (RP), Cone-Rod Dystrophy (CoRD) and Leber Congenital Amaurosis (LCA), of varying severity. In vitro and in vivo assessment of mutant CRX proteins have revealed pathogenic mechanisms for several mutations, but no comprehensive mutation-disease correlation has yet been reported. Here we describe four different classes of disease-causing CRX mutations, characterized by mutation type, pathogenetic mechanism, and the molecular activity of the mutant protein: I) hypomorphic missense mutations with reduced DNA binding, II) antimorphic missense mutations with variable DNA binding, III) antimorphic frameshift/nonsense mutations with intact DNA binding and IV) antimorphic frameshift mutations with reduced DNA binding. Mammalian models representing three of these classes have been characterized. Models carrying Class I mutations display a mild dominant retinal phenotype and recessive LCA, while models carrying Class III and IV mutations display characteristically distinct dominant LCA phenotypes. These animal models also reveal unexpected pathogenic mechanisms underlying CRX-associated retinopathies. The complexity of genotype-phenotype correlation for CRX-associated diseases highlights the value of developing comprehensive 'true-to-disease' animal models for understanding pathologic mechanisms and testing novel therapeutic approaches.

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Identifying pathogenic genetic background of simplex or multiplex retinitis pigmentosa patients: a large scale mutation screening study

Cited by 65 publications

References 34 publications

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Genotype–phenotype correlation and mutation spectrum in a large cohort of patients with inherited retinal dystrophy revealed by next-generation sequencing

Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene

Mechanisms of blindness: Animal models provide insight into distinct CRX‐associated retinopathies

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