Identification of a novel large multigene deletion and a frameshift indel in PDE6B as the underlying cause of early-onset recessive rod-cone degeneration.
Riccardo Sangermano, Pooja Biswas, Lori S Sullivan, Emily M Place, Shyamanga Borooah, Juerg Straubhaar, Eric A Pierce, Stephen P Daiger, Kinga M Bujakowska, Radha Ayaggari
{"title":"Identification of a novel large multigene deletion and a frameshift indel in <i>PDE6B</i> as the underlying cause of early-onset recessive rod-cone degeneration.","authors":"Riccardo Sangermano, Pooja Biswas, Lori S Sullivan, Emily M Place, Shyamanga Borooah, Juerg Straubhaar, Eric A Pierce, Stephen P Daiger, Kinga M Bujakowska, Radha Ayaggari","doi":"10.1101/mcs.a006247","DOIUrl":null,"url":null,"abstract":"<p><p>A family, with two affected identical twins with early-onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare and previously reported causative variant (c.1923_1969delinsTCTGGG; p.Asn643Glyfs*29) in the <i>PDE6B</i> gene in the affected twins and their unaffected father. Further investigation, using genome sequencing, identified a novel ∼7.5-kb deletion (Chr 4:670,405-677,862del) encompassing the <i>ATP5ME</i> gene, part of the 5' UTR of <i>MYL5</i>, and a 378-bp (Chr 4:670,405-670,782) region from the 3' UTR of <i>PDE6B</i> in the affected twins and their unaffected mother. Both variants segregated with disease in the family. Analysis of the relative expression of <i>PDE6B</i>, in peripheral blood cells, also revealed a significantly lower level of <i>PDE6B</i> transcript in affected siblings compared to a normal control. <i>PDE6B</i> is associated with recessive rod-cone degeneration and autosomal dominant congenital stationary night blindness. Ophthalmic evaluation of these patients showed night blindness, fundus abnormalities, and peripheral vision loss, which are consistent with <i>PDE6B</i>-associated recessive retinal degeneration. These findings suggest that the loss of <i>PDE6B</i> transcript resulting from the compound heterozygous pathogenic variants is the underlying cause of recessive rod-cone degeneration in the study family.</p>","PeriodicalId":10360,"journal":{"name":"Cold Spring Harbor Molecular Case Studies","volume":null,"pages":null},"PeriodicalIF":1.8000,"publicationDate":"2022-12-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/f1/fc/MCS006247San.PMC9808551.pdf","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cold Spring Harbor Molecular Case Studies","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/mcs.a006247","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2022/12/1 0:00:00","PubModel":"Print","JCR":"Q3","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
Abstract
A family, with two affected identical twins with early-onset recessive inherited retinal degeneration, was analyzed to determine the underlying genetic cause of pathology. Exome sequencing revealed a rare and previously reported causative variant (c.1923_1969delinsTCTGGG; p.Asn643Glyfs*29) in the PDE6B gene in the affected twins and their unaffected father. Further investigation, using genome sequencing, identified a novel ∼7.5-kb deletion (Chr 4:670,405-677,862del) encompassing the ATP5ME gene, part of the 5' UTR of MYL5, and a 378-bp (Chr 4:670,405-670,782) region from the 3' UTR of PDE6B in the affected twins and their unaffected mother. Both variants segregated with disease in the family. Analysis of the relative expression of PDE6B, in peripheral blood cells, also revealed a significantly lower level of PDE6B transcript in affected siblings compared to a normal control. PDE6B is associated with recessive rod-cone degeneration and autosomal dominant congenital stationary night blindness. Ophthalmic evaluation of these patients showed night blindness, fundus abnormalities, and peripheral vision loss, which are consistent with PDE6B-associated recessive retinal degeneration. These findings suggest that the loss of PDE6B transcript resulting from the compound heterozygous pathogenic variants is the underlying cause of recessive rod-cone degeneration in the study family.
期刊介绍:
Cold Spring Harbor Molecular Case Studies is an open-access, peer-reviewed, international journal in the field of precision medicine. Articles in the journal present genomic and molecular analyses of individuals or cohorts alongside their clinical presentations and phenotypic information. The journal''s purpose is to rapidly share insights into disease development and treatment gained by application of genomics, proteomics, metabolomics, biomarker analysis, and other approaches. The journal covers the fields of cancer, complex diseases, monogenic disorders, neurological conditions, orphan diseases, infectious disease, gene therapy, and pharmacogenomics. It has a rapid peer-review process that is based on technical evaluation of the analyses performed, not the novelty of findings, and offers a swift, clear path to publication. The journal publishes: Research Reports presenting detailed case studies of individuals and small cohorts, Research Articles describing more extensive work using larger cohorts and/or functional analyses, Rapid Communications presenting the discovery of a novel variant and/or novel phenotype associated with a known disease gene, Rapid Cancer Communications presenting the discovery of a novel variant or combination of variants in a cancer type, Variant Discrepancy Resolution describing efforts to resolve differences or update variant interpretations in ClinVar through case-level data sharing, Follow-up Reports linked to previous observations, Plus Review Articles, Editorials, and Position Statements on best practices for research in precision medicine.