Identification of a novel large multigene deletion and a frameshift indel in PDE6B as the underlying cause of early-onset recessive rod-cone degeneration.

IF 1.8 Q3 MEDICINE, RESEARCH & EXPERIMENTAL Cold Spring Harbor Molecular Case Studies Pub Date : 2022-12-28 Print Date: 2022-12-01 DOI:10.1101/mcs.a006247
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
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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.

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PDE6B中一个新的大的多基因缺失和一个移码indel被鉴定为早发性隐性杆锥变性的潜在原因。
对一个有两对患有早发性隐性遗传性视网膜变性的同卵双胞胎的家庭进行了分析,以确定病理学的潜在遗传原因。外显子组测序揭示了受影响双胞胎及其未受影响父亲的PDE6B基因中一种罕见且先前报道的致病变体(c.1923_1969delinsCTGGG;p.Asn643Glyfs*29)。进一步的研究,使用基因组测序,在受影响的双胞胎及其未受影响的母亲中发现了一个新的约7.5-kb的缺失(Chr 4:670405-677862del),包括ATP5ME基因,MYL5的5'UTR的一部分,以及PDE6B的3'UTR的378bp(Chr 4:670405-670782)区域。两种变体都与家族中的疾病分离。对外周血细胞中PDE6B相对表达的分析还显示,与正常对照相比,受影响的兄弟姐妹的PDE6B转录物水平显著较低。PDE6B与隐性视杆锥变性和常染色体显性遗传性先天性静止性夜盲症有关。这些患者的眼科评估显示夜盲症、眼底异常和外周视力丧失,这与PDE6B相关的隐性视网膜变性一致。这些发现表明,由复合杂合致病性变异体引起的PDE6B转录物的丢失是研究家族隐性杆锥变性的根本原因。
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来源期刊
Cold Spring Harbor Molecular Case Studies
Cold Spring Harbor Molecular Case Studies MEDICINE, RESEARCH & EXPERIMENTAL-
CiteScore
3.20
自引率
0.00%
发文量
54
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.
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