Diagnosis for choroideremia in a large Chinese pedigree by next-generation sequencing (NGS) and non-invasive prenatal testing (NIPT)

Leber congenital amaurosis (LCA) is a heterogeneous, early‐onset inherited retinal dystrophy, which is associated with severe visual impairment. We aimed to determine the disease‐causing variants in Iranian LCA and evaluate the clinical implications. Clinically, a possible LCA disease was found through diagnostic imaging, such as fundus photography, autofluorescence and optical coherence tomography. All affected patients showed typical eye symptoms associated with LCA including narrow arterioles, blindness, pigmentary changes and nystagmus. Target exome sequencing was performed to analyse the proband DNA. A homozygous novel c. 2889delT (p.P963 fs) mutation in the RPGRIP1 gene was identified, which was likely the deleterious and pathogenic mutation in the proband. Structurally, this mutation lost a retinitis pigmentosa GTPase regulator (RPGR)‐interacting domain at the C‐terminus which most likely impaired stability in the RPGRIP1 with the distribution of polarised proteins in the cilium connecting process. Sanger sequencing showed complete co‐segregation in this pedigree. This study provides compelling evidence that the c. 2889delT (p.P963 fs) mutation in the RPGRIP1 gene works as a pathogenic mutation that contributes to the progression of LCA.

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“…Here, we used capture agilent probes that were used in previously published studies [21,[26][27][28].…”

Section: Capture Panel Designingmentioning

confidence: 99%

Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing

Imani

Cheng

Mobasher-Jannat

et al. 2017

J Cellular Molecular Medi

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“…Here, we applied targeted next‐generation sequencing (TGS) technology, the most available ‎and promising method available, to identify a novel, homologous mutation of CDHR1 gene in a Chinese family with autosomal recessive retinal dystrophy, extending the gene's mutation spectrum.…”

Section: Introductionmentioning

confidence: 99%

A novel, homozygous nonsense variant of the CDHR1 gene in a Chinese family causes autosomal recessive retinal dystrophy by NGS‐based genetic diagnosis

Cheng

et al. 2018

J Cellular Molecular Medi

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Retinal dystrophy is an inherited, heterogeneous, chronic and progressive disorder of visual functions. The mutations of patients with autosomal recessive retinal retinopathy cone‐and‐rod dysfunction and macular dystrophy have not been well described in the Chinese population. In this study, a three‐generation Chinese retinal dystrophy family was recruited. Ophthalmic examinations were performed. Targeted next generation sequencing (TGS) was used to identify causative genes, and Sanger sequencing was conducted to verify candidate mutations and co‐segregation. Reverse transcription (RT)‐PCR was applied to investigate the spatial and temporal expression patterns of cdhr1 gene in mouse. A novel, homozygous, deleterious and nonsense variant (c.T1641A; p.Y547*) in the CDHR1 gene was identified in the family with autosomal recessive retinal dystrophy, which was co‐segregated with the clinical phenotypes in this family. RT‐PCR analysis revealed that cdhr1 is ubiquitously expressed in eye, particularly very high expression in retina; high expression in lens, sclera, and cornea; and high expression in brain. In conclusion, our study is the first to indicate that the novel homozygous variant c.T1641A (p.Y547*) in the CHDR1 gene might be the disease‐causing mutation for retinal dystrophy in our patient, extending its mutation spectrums. These findings further the understanding of the molecular pathogenesis of this disease and provide new insights for diagnosis as well as new implications for genetic counselling.

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“…The capture Agilent probes were used as in previously published studies [11,12,14,22] with a retinal disease capture panel that included FEVR-related genes: NDP, FZD4, LRP5, TSPAN12, ZNF408, CTNNB1, RCBTB1, and KIF11. In brief, 2 μg of the extracted proband gDNA was randomly sheared by sonication into 300-500 bp fragments.…”

Section: Capture Panel Design and Target Sequencingmentioning

confidence: 99%

“…To identify the disease-causing gene and to identify mutation, TES analyses were performed on the gDNA sample of the proband from pedigree M362 DNA, according to the instructions for Illumina pairedend libraries (Illumina, Inc., San Diego, CA) as reported previously [11,12,14]. The capture Agilent probes were used as in previously published studies [11,12,14,22] with a retinal disease capture panel that included FEVR-related genes: NDP, FZD4, LRP5, TSPAN12, ZNF408, CTNNB1, RCBTB1, and KIF11.…”

Section: Capture Panel Design and Target Sequencingmentioning

confidence: 99%

“…FZD4 mutations in patients with AD FEVR have not been well described in the Chinese population. Here, targeted next-generation sequencing technology, the most available and promising method [11][12][13][14][15][16][17][18] for combined bioinformatics and expression profile analysis, was applied to identify a novel, heterozygous variant of the FZD4 gene in a Chinese family with AD FEVR.…”

Section: Introductionmentioning

confidence: 99%

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A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy

Yang

Cheng

et al. 2018

Cell Physiol Biochem

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Background/Aims: Familial exudative vitreoretinopathy (FEVR) is a complex hereditary eye disorder characterized by incomplete development of the retinal vasculature, thereby affecting retinal angiogenesis. Methods: In this study, a Chinese autosomal dominant FEVR pedigree was recruited. Ophthalmic examinations were performed, targeted next-generation sequencing was used to identify the causative gene, and Sanger sequencing was conducted to verify the candidate mutation. Co-segregation analysis was performed to evaluate pathogenicity. Semi-quantitative reverse transcription-PCR was applied to investigate the spatial and temporal expression patterns of the frizzled class receptor 4 (FZD4) gene in the mouse. Results: A novel heterozygous, deleterious variant of the FZD4 gene, c.A749G (p.Y250C), was identified in this FEVR pedigree, which co-segregated with the clinical phenotype. The amino acid tyrosine (Y) is highly conserved both orthologously and paralogously. The FZD4 gene was highly expressed in the retina, sclera of the eye, ovary, kidney, and liver; ubiquitously expressed in other tissues; and highly expressed in 6 different developmental stages/times of retinal tissue. Conclusion: Our study is the first to identify that the novel heterozygous variant c.A749G (p.Y250C) in the FZD4 gene may be the disease-causing mutation in this FEVR family, extending its mutation spectrum. These findings further our understanding of the molecular pathogenesis of FEVR and will facilitate the development of methods for the diagnosis, prevention, and genetic counseling of this disease.

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Diagnosis for choroideremia in a large Chinese pedigree by next-generation sequencing (NGS) and non-invasive prenatal testing (NIPT)

Cited by 21 publications

References 41 publications

Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing

Identification of a novel RPGRIP1 mutation in an Iranian family with leber congenital amaurosis by exome sequencing

A novel, homozygous nonsense variant of the CDHR1 gene in a Chinese family causes autosomal recessive retinal dystrophy by NGS‐based genetic diagnosis

A Novel Variant of the FZD4 Gene in a Chinese Family Causes Autosomal Dominant Familial Exudative Vitreoretinopathy

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