CDHR1 mutations in retinal dystrophies

Štingl, Katarína; Mayer, Achim; Llavona, Pablo; Mulahasanovic, Lejla; Rudolph, Günther; Jacobson, Samuel G.; Zrenner, Eberhart; Kohl, Susanne; Wissinger, Bernd; Weisschuh, Nicole

doi:10.1038/s41598-017-07117-8

Cited by 48 publications

(49 citation statements)

References 33 publications

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“…The patient with an absence of bone spicule pigmentation was relatively young and carried disease-causing mutations in CDHR1, which is known to cause a delayed-onset retinal degeneration; thus, the patient will likely develop bone spicule pigmentation later in life. 11,36 Asymmetric disease manifestation was observed in two female patients with sporadic RP in whom only one eye was suggestive for their X-linked carrier status, likely due to skewed X-inactivation in the more severely affected eye. 37 The uncommon findings on retinal imaging in patients without identified mutations could reflect atypical genotype-phenotype correlations, specific effects of as yet genetic testing may increase the likelihood to identify disease-causing mutations.…”

Section: Discussionmentioning

confidence: 97%

“…Re‐evaluating patients with atypical findings and identified mutations revealed potential explanations: Patients with an early‐onset central retinal atrophy exhibited RDH12 and CRB1 related retinopathy, both of which are known to be associated with such a phenotype. The patient with an absence of bone spicule pigmentation was relatively young and carried disease‐causing mutations in CDHR1 , which is known to cause a delayed‐onset retinal degeneration; thus, the patient will likely develop bone spicule pigmentation later in life . Asymmetric disease manifestation was observed in two female patients with sporadic RP in whom only one eye was suggestive for their X‐linked carrier status, likely due to skewed X‐inactivation in the more severely affected eye .…”

Section: Discussionmentioning

confidence: 99%

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Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Birtel

Gliem

Oishi

et al. 2019

Clinical Exper Ophthalmology

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Importance Uncommon characteristics in genetically unsolved retinitis pigmentosa (RP) patients may indicate an incorrect clinical diagnosis or as yet unknown genetic causes resulting in specific retinal phenotypes. The diagnostic yield of targeted next‐generation sequencing may be increased by a reasonable preselection of RP‐patients. Background To systematically evaluate and compare features of genetically solved and unsolved RP‐patients. Design Retrospective, observational study. Participants One‐hundred and twelve consecutive RP‐patients who underwent extensive molecular genetic analysis. Methods Characterization of patients based on multimodal imaging and medical history. Main Outcome Measures Differences between genetically solved and unsolved RP‐patients. Results Compared to genetically solved patients (n = 77), genetically unsolved patients (n = 35) more frequently had an age of disease‐onset above 30 years (60% vs 8%; P < 0.0001), showed atypical fundus features (49% vs 8%; P < 0. 0001) and indicators for phenocopies (eg, autoimmune diseases) (17% vs 0%; P < 0. 001). Evidence for a particular inheritance pattern was less common (20% vs 49%; P < 0. 01). The diagnostic yield was 84% (71/85) in patients with first symptoms below 30 years‐of‐age, compared to 69% (77/112) in the overall cohort. The other selection criteria alone or in combination resulted in limited further increase of the diagnostic yield (up to 89%) while excluding considerably more patients (up to 56%) from genetic testing. Conclusions and Relevance The medical history and retinal phenotype differ between genetically solved and a subgroup of unsolved RP‐patients, which may reflect undetected genotypes or retinal conditions mimicking RP. Patient stratification may inform on the individual likelihood of identifying disease‐causing mutations and may impact patient counselling.

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Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Birtel

Gliem

Oishi

et al. 2019

Clinical Exper Ophthalmology

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“…In literatures, different autosomal recessive phenotypes have been associated with the CDHR1 gene mutations, ranging from RP to CRD although the relationship between phenotypes and gene mutations are variable . The proband in our study, with a loss of more than one‐thirds of CDHR1 by a homozygous and nonsense variant p.Y547*, has been noticed the simultaneous onset of dark adaptation difficulties, trouble with color vision, and light sensitivity at age of 24; ERG in different waves showed markedly reduced rod‐and‐cone responses; FP/FPP showed macular dysdrophy (MD).…”

Section: Discussionmentioning

confidence: 51%

“…Clinically, this patient presented MD/CRD. Thus, combined with our study, patients with CDHR1 truncated protein by nonsense, splicing variants or deletions with frameshift, other than missense variants, might cause more severely phenotypes, such as MD/CRD, and/or earlier disease onset …”

Section: Discussionmentioning

confidence: 53%

“…The pathogenic CDHR1 mutation was first identified in 2010, and only a few mutations have been reported since then . Very recently, six CDHR1 mutations were also identified in Germany for macular and cone/cone‐rod dystrophies or retinal dystrophy . These small amounts of mutations suggest that the mutations in the CDHR1 gene are a rare case of arCRD (autosomal recessive cone‐rod dystrophy) in Western countries .…”

Section: Discussionmentioning

confidence: 99%

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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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Genetic Linkage Mapping

Imai‐Okazaki

Ott

2018

Encyclopedia of Life Sciences

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Random occurrences of crossovers along a chromosome permit definition of a genetic distance. Such distances are used to create genetic maps and localise disease genes on these maps. Human genetic maps consist of dense sets of DNA polymorphisms, notably single‐nucleotide polymorphisms (SNPs) and, resulting from DNA sequencing, single‐nucleotide variants (SNVs). The main application of linkage mapping is to localise hypothesised disease genes on the human marker maps, which in turn represents the first step towards understanding of disease aetiology. While linkage analysis represents the mainstay for genetic mapping, newer approaches have been developed, for example, methods allowing the use of a single affected individual in conjunction with a number of control individuals, a situation not tractable by standard linkage and genetic association analyses. Key Concepts Genetic distances are based on the random occurrence of crossovers along a chromosome, and a crossover will lead to a recombination in half of the gametes. Genetic loci in close proximity will rarely experience a recombination between them, so the recombination fraction will be small. For short distances, the recombination fraction represents genetic distance in units of Morgans. DNA sequencing has established the order of variants on a chromosome, so genetic linkage mapping essentially aims to measure distances in each interval (between two adjacent variants) on a chromosome. Disease gene mapping hypothesises the presence of a disease locus, for which genetic distances to one after another genetic variant are estimated. A significantly small such distance (recombination fraction significantly smaller than 50%) establishes genetic linkage between the disease locus and a given variant.

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CDHR1 mutations in retinal dystrophies

Cited by 48 publications

References 33 publications

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

Genetic testing in patients with retinitis pigmentosa: Features of unsolved cases

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

Genetic Linkage Mapping

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