Dataset Information

Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy.

ABSTRACT:

Purpose

The purpose of this study was to elucidate the genetic basis of 2 distinct phenotypes associated with biallelic variants in RDH12.

Methods

Patients with biallelic variants in RDH12 were recruited from our genetic eye clinic. Ocular phenotypes were evaluated. Genotype-phenotype correlations were further clarified using in-house and existing databases.

Results

In total, 22 biallelic RDH12 variants, including 5 novel variants, were identified in 29 patients from 27 families. Two distinct phenotypes were observed: early-onset and generalized retinal dystrophy with severe impairment of rods and cones in 24 patients (82.8%, 24/29), and late-onset cone-rod dystrophy (CORD) with central macular atrophy in 5 patients from 5 unrelated families (17.2%, 5/29), in which a hypomorphic allele (c.806C>G/p.Ala269Gly) was shared by all 5 patients. During follow-up, patients with late-onset CORD were relatively stable and did not progress to the severe form, which was considered to be an independent manifestation of RDH12-associated retinopathy caused by specific genotypes.

Conclusions

The hypomorphic allele is responsible for the unique late-onset CORD in 5 families with recessive RDH12-associated retinopathy, in contrast to the well-known severe and generalized retinopathy. Determining the therapeutic value of interventions may depend on understanding the molecular mechanisms underlying manifestation of this hypomorphic variant only in the central macular region, with relative preservation of the peripheral retina.

SUBMITTER: Wang J

PROVIDER: S-EPMC9419460 | biostudies-literature | 2022 Aug

REPOSITORIES: biostudies-literature

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Publications

Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy.

Wang Junwen J Wang Yingwei Y Li Shiqiang S Xiao Xueshan X Yi Zhen Z Jiang Yi Y Li Xueqing X Jia Xiaoyun X Wang Panfeng P Jin Chenjin C Sun Wenmin W Zhang Qingjiong Q

Investigative ophthalmology & visual science 20220801 9

<h4>Purpose</h4>The purpose of this study was to elucidate the genetic basis of 2 distinct phenotypes associated with biallelic variants in RDH12.<h4>Methods</h4>Patients with biallelic variants in RDH12 were recruited from our genetic eye clinic. Ocular phenotypes were evaluated. Genotype-phenotype correlations were further clarified using in-house and existing databases.<h4>Results</h4>In total, 22 biallelic RDH12 variants, including 5 novel variants, were identified in 29 patients from 27 fam ...[more]

PMID: 35994252

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Project description:ImportanceThe families evaluated in this study represent the second report of cone-rod dystrophy (CRD) cases caused by mutations in RAB28, a recently discovered gene associated with CRD.ObjectiveTo determine the disease-causing gene in 2 families of Spanish descent presenting with CRD who do not have ABCA4 mutations.Design, setting, and participantsMolecular genetics and observational case studies of 2 families, each with 1 affected proband with CRD and 3 or 5 unaffected family members. The affected individual from each family received a complete ophthalmic examination including assessment of refractive errors and best-corrected visual acuity, biomicroscopy, color fundus photography, electroretinography analysis, and visual-evoked potential analysis. After complete sequencing of the ABCA4 gene with negative results, the screening for disease-causing mutations was performed by whole-exome sequencing. Possible disease-associated variants were determined by filtering based on minor allele frequency, predicted pathogenicity, and segregation analysis in all family members.Main outcomes and measuresThe appearance of the macula was evaluated by clinical examination, fundus photography, and fundus autofluorescence imaging, and visual function was assessed by electroretinography. Disease-causing mutations were assessed by sequence analyses.ResultsOphthalmologic findings included markedly reduced visual acuity, bull's eye maculopathy, foveal hyperpigmentation, peripapillary atrophy, dyschromatopsia, extinguished photopic responses, and reduced scotopic responses observed on electroretinography consistent with the CRD phenotype often associated with ABCA4 mutations. Although no ABCA4 mutations were detected in either patient, whole-exome sequencing analysis identified 2 new homozygous mutations in the recently described RAB28 gene, the c.172 + 1G>C splice site variant in IVS2 and the missense c.T651G:p.C217W substitution. Both variants were determined as deleterious by predictive programs and were segregated with the disease in both families. Sequencing of 107 additional patients of Spanish descent with CRD did not reveal other cases with RAB28 mutations.Conclusions and relevanceDeleterious mutations in RAB28 result in a classic CRD phenotype and are an infrequent cause of CRD in the Spanish population.

Project description:To identify the causative mutation in a canine cone-rod dystrophy (crd3) that segregates as an adult onset disorder in the Glen of Imaal Terrier breed of dog.Glen of Imaal Terriers were ascertained for crd3 phenotype by clinical ophthalmoscopic examination, and in selected cases by electroretinography. Blood samples from affected cases and non-affected controls were collected and used, after DNA extraction, to undertake a genome-wide association study using Affymetrix Version 2 Canine single nucleotide polymorphism chips and 250K Sty Assay protocol. Positional candidate gene analysis was undertaken for genes identified within the peak-association signal region. Retinal morphology of selected crd3-affected dogs was evaluated by light and electron microscopy.A peak association signal exceeding genome-wide significance was identified on canine chromosome 16. Evaluation of genes in this region suggested A Disintegrin And Metalloprotease domain, family member 9 (ADAM9), identified concurrently elsewhere as the cause of human cone-rod dystrophy 9 (CORD9), as a strong positional candidate for canine crd3. Sequence analysis identified a large genomic deletion (over 20 kb) that removed exons 15 and 16 from the ADAM9 transcript, introduced a premature stop, and would remove critical domains from the encoded protein. Light and electron microscopy established that, as in ADAM9 knockout mice, the primary lesion in crd3 appears to be a failure of the apical microvilli of the retinal pigment epithelium to appropriately invest photoreceptor outer segments. By electroretinography, retinal function appears normal in very young crd3-affected dogs, but by 15 months of age, cone dysfunction is present. Subsequently, both rod and cone function degenerate.Identification of this ADAM9 deletion in crd3-affected dogs establishes this canine disease as orthologous to CORD9 in humans, and offers opportunities for further characterization of the disease process, and potential for genetic therapeutic intervention.

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Dataset Information

Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy.

Purpose

Methods

Results

Conclusions

Publications

Clinical and Genetic Analysis of RDH12-Associated Retinopathy in 27 Chinese Families: A Hypomorphic Allele Leads to Cone-Rod Dystrophy.

Similar Datasets

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