Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies

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Abstract

Background

Birth defects are responsible for approximately 7% of neonatal deaths worldwide by World Health Organization in 2004. Many methods have been utilized for examining the congenital anomalies in fetuses. This study aims to investigate the efficiency of simultaneous CNV-seq and whole-exome sequencing (WES) in the diagnosis of fetal anomaly based on a large Chinese cohort.

Methods

In this cohort study, 1800 pregnant women with singleton fetus in Hubei Province were recruited from 2018 to 2020 for prenatal ultrasonic screening. Those with fetal structural anomalies were transferred to the Maternal and Child Health Hospital of Hubei Province through a referral network in Hubei, China. After multidisciplinary consultation and decision on fetal outcome, products of conception (POC) samples were obtained. Simultaneous CNV-seq and WES was conducted to identify the fetal anomalies that can compress initial DNA and turnaround time of reports.

Results

In total, 959 couples were finally eligible for the enrollment. A total of 227 trios were identified with a causative alteration (CNV or variant), among which 191 (84.14%) were de novo. Double diagnosis of pathogenic CNVs and variants have been identified in 10 fetuses. The diagnostic yield of multisystem anomalies was significantly higher than single system anomalies (32.28% vs. 22.36%, P = 0.0183). The diagnostic rate of fetuses with consistent intra- and extra-uterine phenotypes (172/684) was significantly higher than the rate of these with inconsistent phenotypes (17/116, P = 0.0130).

Conclusions

Simultaneous CNV-seq and WES analysis contributed to fetal anomaly diagnosis and played a vital role in elucidating complex anomalies with compound causes.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12967-021-03202-9.

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Most cited references 43

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Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Sue Richards, Nazneen Aziz, Sherri Bale … (2015)

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants. 1 In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next generation sequencing. By adopting and leveraging next generation sequencing, clinical laboratories are now performing an ever increasing catalogue of genetic testing spanning genotyping, single genes, gene panels, exomes, genomes, transcriptomes and epigenetic assays for genetic disorders. By virtue of increased complexity, this paradigm shift in genetic testing has been accompanied by new challenges in sequence interpretation. In this context, the ACMG convened a workgroup in 2013 comprised of representatives from the ACMG, the Association for Molecular Pathology (AMP) and the College of American Pathologists (CAP) to revisit and revise the standards and guidelines for the interpretation of sequence variants. The group consisted of clinical laboratory directors and clinicians. This report represents expert opinion of the workgroup with input from ACMG, AMP and CAP stakeholders. These recommendations primarily apply to the breadth of genetic tests used in clinical laboratories including genotyping, single genes, panels, exomes and genomes. This report recommends the use of specific standard terminology: ‘pathogenic’, ‘likely pathogenic’, ‘uncertain significance’, ‘likely benign’, and ‘benign’ to describe variants identified in Mendelian disorders. Moreover, this recommendation describes a process for classification of variants into these five categories based on criteria using typical types of variant evidence (e.g. population data, computational data, functional data, segregation data, etc.). Because of the increased complexity of analysis and interpretation of clinical genetic testing described in this report, the ACMG strongly recommends that clinical molecular genetic testing should be performed in a CLIA-approved laboratory with results interpreted by a board-certified clinical molecular geneticist or molecular genetic pathologist or equivalent.

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Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)

Erin Rooney Riggs, Erica Andersen, Athena Cherry … (2019)

Copy number analysis to detect disease-causing losses and gains across the genome is recommended for the evaluation of individuals with neurodevelopmental disorders and/or multiple congenital anomalies, as well as for fetuses with ultrasound abnormalities. In the decade that this analysis has been in widespread clinical use, tremendous strides have been made in understanding the effects of copy number variants (CNVs) in both affected individuals and the general population. However, continued broad implementation of array- and next-generation sequencing-based technologies will expand the types of CNVs encountered in the clinical setting, as well as our understanding of their impact on human health. To assist clinical laboratories in the classification and reporting of CNVs, irrespective of the technology used to identify them, the American College of Medical Genetics and Genomics has developed the following professional standards in collaboration with the NIH-funded Clinical Genome Resource (ClinGen) project. This update introduces a quantitative, evidence-based scoring framework; encourages the implementation of the 5-tier classification system widely used in sequence variant classification; and recommends “uncoupling” the evidence-based classification of a variant from its potential implications for a particular individual. These professional standards will guide the evaluation of constitutional CNVs and encourage consistency and transparency across clinical laboratories.

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ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

Robert C Green, Jonathan S Berg, Wayne W Grody … (2013)

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the patient to the possibility of such results in pretest patient discussions, clinical testing, and reporting of results. The ACMG appointed a Working Group on Incidental Findings in Clinical Exome and Genome Sequencing to make recommendations about responsible management of incidental findings when patients undergo exome or genome sequencing. This Working Group conducted a year-long consensus process, including an open forum at the 2012 Annual Meeting and review by outside experts, and produced recommendations that have been approved by the ACMG Board. Specific and detailed recommendations, and the background and rationale for these recommendations, are described herein. The ACMG recommends that laboratories performing clinical sequencing seek and report mutations of the specified classes or types in the genes listed here. This evaluation and reporting should be performed for all clinical germline (constitutional) exome and genome sequencing, including the "normal" of tumor-normal subtractive analyses in all subjects, irrespective of age but excluding fetal samples. We recognize that there are insufficient data on penetrance and clinical utility to fully support these recommendations, and we encourage the creation of an ongoing process for updating these recommendations at least annually as further data are collected.

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Author and article information

Contributors

Longxian Cheng: chenglongxian@sina.com

Juntao Liu:

ORCID: http://orcid.org/0000-0001-9978-7031

liujt@pumch.cn

Journal

Journal ID (nlm-ta): J Transl Med

Journal ID (iso-abbrev): J Transl Med

Title: Journal of Translational Medicine

Publisher: BioMed Central (London )

ISSN (Electronic): 1479-5876

Publication date (Electronic): 3 January 2022

Publication date PMC-release: 3 January 2022

Publication date Collection: 2022

Volume: 20

Electronic Location Identifier: 10

Affiliations

[1 ]GRID grid.440222.2, ISNI 0000 0004 6005 7754, Department of Ultrasound Diagnosis, , Maternal and Child Health Hospital of Hubei Province, ; Wuhan, 430070 Hubei China

[2 ]GRID grid.413106.1, ISNI 0000 0000 9889 6335, Department of Obstetrics and Gynecology, State Key Laboratory of Complex Severe and Rare Diseases, , Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, ; Beijing, 100730 China

[3 ]Berry Genomics Corporation, Beijing, 102200 China

[4 ]GRID grid.440222.2, ISNI 0000 0004 6005 7754, Department of Obstetrics, , Maternal and Child Health Hospital of Hubei Province, ; Wuhan, 430070 Hubei China

[5 ]GRID grid.440222.2, ISNI 0000 0004 6005 7754, Department of Genetic Laboratory, , Maternal and Child Health Hospital of Hubei Province, ; Wuhan, 430070 Hubei China

[6 ]GRID grid.440222.2, ISNI 0000 0004 6005 7754, Department of Ultrasound Diagnosis, , Hubei Maternity and Child Health Hospital, ; No. 745, Wuluo Road, Hongshan District, Wuhan, 430030 Hubei China

[7 ]GRID grid.506261.6, ISNI 0000 0001 0706 7839, Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, , Peking Union Medical College and Chinese Academy of Medical Sciences, ; No. 1, Shuaifu Garden, Dongcheng District, Beijing, 100730 China

Author information

Juntao Liu http://orcid.org/0000-0001-9978-7031

Article

Publisher ID: 3202

DOI: 10.1186/s12967-021-03202-9

PMC ID: 8722033

PubMed ID: 34980134

SO-VID: e6f4c960-5c6d-40b4-a617-04eeb73ef274

License:

Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 23 September 2021

Date accepted : 16 December 2021

Funding

Funded by: CAMS Innovation Fund for Medical Sciences (CIFMS)

Award ID: 2020-I2M-C

Award ID: T-B-046

Award Recipient : Juntao Liu

Funded by: National Key R&D Program of China

Award ID: 2019YFC1005105

Award Recipient : Juntao Liu

Funded by: Hubei Province health and family planning scientific research project

Award ID: WJ2018H0132

Award ID: WJ2017Z019

Award Recipient : Xinlin Chen

Funded by: Hubei Province Natural Science Foundation

Award ID: 2020CFB164

Award Recipient : Xinlin Chen

Funded by: Key R&D Program of Hubei Science and Technology Department

Award ID: 2020BCB002

Award Recipient : Xinlin Chen

Funded by: Key Program of Hubei Science and Technology Department aiding Xinjiang and Tibet Province

Award ID: 2018AKB1496

Award Recipient : Xinlin Chen

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ScienceOpen disciplines: Medicine

Keywords: whole-exome sequencing,prenatal diagnosis,cnv-seq,structural anomaly

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ScienceOpen disciplines: Medicine

Keywords: whole-exome sequencing, prenatal diagnosis, cnv-seq, structural anomaly

Clinical efficiency of simultaneous CNV-seq and whole-exome sequencing for testing fetal structural anomalies

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Most cited references 43

Standards and Guidelines for the Interpretation of Sequence Variants: A Joint Consensus Recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology

Technical standards for the interpretation and reporting of constitutional copy number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen)

ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.

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