تقرير
Long-read genome sequencing reveals a novel intronic retroelement insertion in NR5A1 associated with 46,XY differences of sexual development.
| العنوان: | Long-read genome sequencing reveals a novel intronic retroelement insertion in NR5A1 associated with 46,XY differences of sexual development. |
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| المؤلفون: | Del Gobbo GF; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada., Wang X; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada., Couse M; Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Canada., Mackay L; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada., Goldsmith C; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada., Marshall AE; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada., Liang Y; Centre for Computational Medicine, The Hospital for Sick Children, Toronto, Canada., Lambert C; PacBio of California, Inc, Menlo Park, California, USA., Zhang S; PacBio of California, Inc, Menlo Park, California, USA., Dhillon H; PacBio of California, Inc, Menlo Park, California, USA., Fanslow C; PacBio of California, Inc, Menlo Park, California, USA., Rowell WJ; PacBio of California, Inc, Menlo Park, California, USA., Marshall CR; Division of Genome Diagnostics, The Hospital for Sick Children, Toronto, Canada., Kernohan KD; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.; Newborn Screening Ontario, Ottawa, Canada., Boycott KM; Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada. |
| مؤلفون مشاركون: | Care4Rare Canada Consortium; Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Canada. |
| المصدر: | American journal of medical genetics. Part A [Am J Med Genet A] 2024 May; Vol. 194 (5), pp. e63522. Date of Electronic Publication: 2023 Dec 22. |
| نوع المنشور: | Case Reports; Research Support, Non-U.S. Gov't |
| اللغة: | English |
| بيانات الدورية: | Publisher: Wiley-Blackwell Country of Publication: United States NLM ID: 101235741 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1552-4833 (Electronic) Linking ISSN: 15524825 NLM ISO Abbreviation: Am J Med Genet A Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Hoboken, N.J. : Wiley-Blackwell Original Publication: Hoboken, N.J. : Wiley-Liss, c2003- |
| مواضيع طبية MeSH: | Retroelements*/genetics , Disorder of Sex Development, 46,XY*/genetics, Humans ; Mutation ; Introns/genetics ; Rare Diseases/genetics ; Sexual Development ; Steroidogenic Factor 1/genetics |
| مستخلص: | Despite significant advancements in rare genetic disease diagnostics, many patients with rare genetic disease remain without a molecular diagnosis. Novel tools and methods are needed to improve the detection of disease-associated variants and understand the genetic basis of many rare diseases. Long-read genome sequencing provides improved sequencing in highly repetitive, homologous, and low-complexity regions, and improved assessment of structural variation and complex genomic rearrangements compared to short-read genome sequencing. As such, it is a promising method to explore overlooked genetic variants in rare diseases with a high suspicion of a genetic basis. We therefore applied PacBio HiFi sequencing in a large multi-generational family presenting with autosomal dominant 46,XY differences of sexual development (DSD), for whom extensive molecular testing over multiple decades had failed to identify a molecular diagnosis. This revealed a rare SINE-VNTR-Alu retroelement insertion in intron 4 of NR5A1, a gene in which loss-of-function variants are an established cause of 46,XY DSD. The insertion segregated among affected family members and was associated with loss-of-expression of alleles in cis, demonstrating a functional impact on NR5A1. This case highlights the power of long-read genome sequencing to detect genomic variants that have previously been intractable to detection by standard short-read genomic testing. (© 2023 Wiley Periodicals LLC.) |
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| معلومات مُعتمدة: | Canada CIHR; Canada CIHR |
| فهرسة مساهمة: | Keywords: HiFi sequencing; NR5A1; differences of sexual development; long‐read sequencing; retrotransposon |
| المشرفين على المادة: | 0 (Retroelements) 0 (Steroidogenic Factor 1) 0 (NR5A1 protein, human) |
| تواريخ الأحداث: | Date Created: 20231222 Date Completed: 20240411 Latest Revision: 20240812 |
| رمز التحديث: | 20240813 |
| DOI: | 10.1002/ajmg.a.63522 |
| PMID: | 38131126 |
| قاعدة البيانات: | MEDLINE |
| تدمد: | 1552-4833 |
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| DOI: | 10.1002/ajmg.a.63522 |