Startseite Clinical utility of regions of homozygosity (ROH) identified in exome sequencing: when to pursue confirmatory uniparental disomy testing for imprinting disorders?
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Clinical utility of regions of homozygosity (ROH) identified in exome sequencing: when to pursue confirmatory uniparental disomy testing for imprinting disorders?

  • Xiaoyan Huo , Xinyi Lu , Deyun Lu , Huili Liu , Yi Liu , Qianfeng Zhao , Yu Sun , Weiqian Dai , Wenjuan Qiu , Yongguo Yu ORCID logo EMAIL logo und Yanjie Fan EMAIL logo
Veröffentlicht/Copyright: 19. Juli 2024
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Clinical Chemistry and Laboratory Medicine (CCLM)
Aus der Zeitschrift Clinical Chemistry and Laboratory Medicine (CCLM) Band 63 Heft 1

Abstract

Objectives

Regions of homozygosity (ROH) could implicate uniparental disomy (UPD) on specific chromosomes associated with imprinting disorders. Though the algorithms for ROH detection in exome sequencing (ES) have been developed, optimal reporting thresholds and when to pursue confirmatory UPD testing for imprinting disorders remain in ambiguity. This study used a data-driven approach to assess optimal reporting thresholds of ROH in clinical practice.

Methods

ROH analysis was performed using Automap in a retrospective cohort of 8,219 patients and a prospective cohort of 1,964 patients with ES data. Cases with ROH on imprinting-disorders related chromosomes were selected for additional methylation-specific confirmatory testing. The diagnostic yield, the ROH pattern of eventually diagnosed cases and optimal thresholds for confirmatory testing were analyzed.

Results

In the retrospective analysis, 15 true UPD cases of imprinting disorders were confirmed among 51 suspected cases by ROH detection. Pattern of ROH differed between confirmed UPD and non-UPD cases. Maximized yield and minimized false discovery rate of confirmatory UPD testing was achieved at the thresholds of >20 Mb or >25 % chromosomal coverage for interstitial ROH, and >5 Mb for terminal ROH. Current recommendation by ACMG was nearly optimal, though refined thresholds as proposed in this study could reduce the workload by 31 % without losing any true UPD diagnosis. Our refined thresholds remained optimal after independent evaluation in a prospective cohort.

Conclusions

ROH identified in ES could implicate the presence of clinically relevant UPD. This study recommended size and coverage thresholds for confirmatory UPD testing after ROH detection in ES, contributing to the development of evidence-based reporting guidelines.

Keywords: regions of homozygosity (ROH); exome sequencing; uniparental disomy; genetic testing
Corresponding authors: Yongguo Yu and Yanjie Fan, Clinical Genetics Center, Shanghai Institute for Pediatric Research, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200092, China, E-mail: (Y. Yu), (Y. Fan)

Funding source: National Key Research and Development Program of China

Award Identifier / Grant number: No.2022YFC2703400

Award Identifier / Grant number: No.2022YFC2703405

Funding source: National Natural Science Foundation of China

Award Identifier / Grant number: No.82171165 and 81873735

Award Identifier / Grant number: No.82271904 and 82070914

Acknowledgments

We would like to acknowledge the affected individuals and their families for the participation in the study.

  1. Research ethics: This study was approved by the Ethics Committee of Xinhua Hospital (Shanghai, China).

  2. Informed consent: Informed consent was obtained from participants or their parents.

  3. Author contributions: XYH, YGY and YJF contributed to the study conception and design. XYH and YJF conducted experiments, analyzed data and wrote the manuscript. QFZ, WQD and YL conducted experiments and analyzed data. HLL, YS, XYL, XYH and YJF analyzed the exome sequencing data. DYL, WJQ and YGY participated in the clinical evaluation of patients and data acquisition. All authors reviewed the manuscript. All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  4. Competing interests: The authors state no conflict of interest.

  5. Research funding: This work was sponsored by the grants to YF (NSF No. 82171165 & 81873735; 2022YFC2703405), and to YGY the National Key R&D Program of China (No.2022YFC2703400), the National Natural Science Foundation of China (No.82271904 and 82070914).

  6. Data availability: Not applicable.

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Supplementary Material

This article contains supplementary material (https://doi.org/10.1515/cclm-2024-0239).

Received: 2024-02-22
Accepted: 2024-07-07
Published Online: 2024-07-19
Published in Print: 2025-01-29

© 2024 Walter de Gruyter GmbH, Berlin/Boston

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https://doi.org/10.1515/cclm-2024-0239
Schlagwörter für diesen Artikel
regions of homozygosity (ROH); exome sequencing; uniparental disomy; genetic testing

Artikel in diesem Heft

  1. Frontmatter
  2. Editorial
  3. Blood self-sampling: friend or foe?
  4. Reviews
  5. Blood self-sampling devices: innovation, interpretation and implementation in total lab automation
  6. Salivary fatty acids in humans: a comprehensive literature review
  7. Opinion Papers
  8. EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) recommendations for reinforcing cyber-security and managing cyber-attacks in medical laboratories
  9. Point-of-care testing: state-of-the art and perspectives
  10. A standard to report biological variation data studies – based on an expert opinion
  11. Ethical Checklists for Clinical Research Projects and Laboratory Medicine: two tools to evaluate compliance with bioethical principles in different settings
  12. Guidelines and Recommendations
  13. Assessment of cardiovascular risk and physical activity: the role of cardiac-specific biomarkers in the general population and athletes
  14. Genetics and Molecular Diagnostics
  15. Clinical utility of regions of homozygosity (ROH) identified in exome sequencing: when to pursue confirmatory uniparental disomy testing for imprinting disorders?
  16. An ultrasensitive DNA-enhanced amplification method for detecting cfDNA drug-resistant mutations in non-small cell lung cancer with selective FEN-assisted degradation of dominant somatic fragments
  17. General Clinical Chemistry and Laboratory Medicine
  18. The biological variation of insulin resistance markers: data from the European Biological Variation Study (EuBIVAS)
  19. The surveys on quality indicators for the total testing process in clinical laboratories of Fujian Province in China from 2018 to 2023
  20. Preservation of urine specimens for metabolic evaluation of recurrent urinary stone formers
  21. Performance evaluation of a smartphone-based home test for fecal calprotection
  22. Implications of monoclonal gammopathy and isoelectric focusing pattern 5 on the free light chain kappa diagnostics in cerebrospinal fluid
  23. Development and validation of a novel 7α-hydroxy-4-cholesten-3-one (C4) liquid chromatography tandem mass spectrometry method and its utility to assess pre-analytical stability
  24. Establishment of ELISA-comparable moderate and high thresholds for anticardiolipin and anti-β2 glycoprotein I chemiluminescent immunoassays according to the 2023 ACR/EULAR APS classification criteria and evaluation of their diagnostic performance
  25. Reference Values and Biological Variations
  26. Capillary blood parameters are gestational age, birthweight, delivery mode and gender dependent in healthy preterm and term infants
  27. Reference intervals and percentiles for soluble transferrin receptor and sTfR/log ferritin index in healthy children and adolescents
  28. Cancer Diagnostics
  29. Detection of serum CC16 by a rapid and ultrasensitive magnetic chemiluminescence immunoassay for lung disease diagnosis
  30. Cardiovascular Diseases
  31. The role of functional vitamin D deficiency and low vitamin D reservoirs in relation to cardiovascular health and mortality
  32. Annual Reviewer Acknowledgment
  33. Reviewer Acknowledgment
  34. Letters to the Editor
  35. EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) survey on cybersecurity
  36. Comment on Lippi et al.: EFLM Task Force Preparation of Labs for Emergencies (TF-PLE) recommendations for reinforcing cyber-security and managing cyber-attacks in medical laboratories
  37. Six Sigma in laboratory medicine: the unfinished symphony
  38. Navigating complexities in vitamin D and cardiovascular health: a call for comprehensive analysis
  39. Simplified preanalytical laboratory procedures for therapeutic drug monitoring (TDM) in patients treated with high-dose methotrexate (HD-MTX) and glucarpidase
  40. New generation of Abbott enzyme assays: imprecision, methods comparison, and impact on patients’ results
  41. Correction of negative-interference from calcium dobesilate in the Roche sarcosine oxidase creatinine assay using CuO
  42. Two cases of MTHFR C677T polymorphism typing failure by Taqman system due to MTHFR 679 GA heterozygous mutation
  43. A falsely elevated blood alcohol concentration (BAC) related to an intravenous administration of phenytoin sodium
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