Clinical application of fetal genome-wide sequencing during pregnancy: position statement of the Canadian College of Medical Geneticists

Purpose and scopeThe aim of this position statement is to provide recommendations for Canadian healthcare professionals regarding the use of genome-wide sequencing (GWS) in the context of diagnostic testing of the fetus during pregnancy. This statement was developed to facilitate clinical translation of GWS as a prenatal diagnostic test and the development of best practices in Canada, but the applicability of this document is broader and aims to help professionals in other healthcare systems.Methods of statement developmentA multidisciplinary group was assembled to review existing literature on fetal GWS for genetic diagnosis in the context of suspected monogenic diseases and to make recommendations relevant to the Canadian context. The statement was circulated for comments to the Canadian College of Medical Geneticists (CCMG) membership-at-large and, following incorporation of feedback, approved by the CCMG Board of Directors on 19 February 2021.Results and conclusionsThe use of prenatal GWS is indicated for the investigation of multiple fetal anomalies. Its use in the context of isolated fetal anomaly should be guided by available resources and current evidence, which is continually changing. During pregnancy, GWS should be ordered by, or in collaboration with, a medical geneticist. It should be used following detailed phenotyping to interrogate known disease genes, preferably using a trio approach, following detailed fetal phenotyping. Testing should be done with an overall aim to help in the management of the pregnancy, delivery and postnatal care. It should be guided by personal utility of the test for the pregnant person and clinical utility for pregnancy and birth management, as outlined herein. Genetic counselling is crucial in making the parental decision an informed decision. Chromosomal microarray analysis should be completed in parallel or prior to GWS and should be preceded by Quantitative Fluorescent PCR (QF-PCR) for detection of common aneuploidies. In normal circumstances, only pathogenic and likely pathogenic variants with a high likelihood of being associated with the identified fetal anomalies should be reported. Reporting of secondary findings, defined as purposeful analysis of variants in a set of medically actionable genes, should not, by default, be performed in the prenatal context. Laboratories should only report incidental findings that reveal risk of a significant Mendelian condition during infancy and childhood. Should a laboratory have a policy for reporting incidental findings in medically actionable adult-onset conditions, they should only be reported with explicit opt-in consent signed by the tested individuals. Genetic counselling is crucial in disclosing the test results and the implications the results may have for the fetus. It should be emphasised that negative results do not rule out a genetic diagnosis nor guarantee a good prognosis. Postnatal phenotyping and reanalysis of existing data should be considered. Families should be given the opportunity to participate in research studies as appropriate. These recommendations will be routinely re-evaluated as knowledge of the diagnostic and clinical utility of fetal GWS during pregnancy improves.

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Attitudes of Researchers to the Return of Incidental and Targeted Genomic Findings Obtained in a Research Setting to Participants

Blood ◽

10.1182/blood.v120.21.2069.2069 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2069-2069

Author(s):

Conrad V Fernandez ◽

Denise Avard ◽

Bartha Knoppers ◽

Colleen O'Connell ◽

David Malkin ◽

...

Keyword(s):

Genetic Counselling ◽

Incidental Findings ◽

Clinical Utility ◽

Genomic Research ◽

Data Set ◽

Research Results ◽

Ethics Review ◽

Institutional Ethics ◽

Wide Range ◽

Genomic Results

Abstract Abstract 2069 Background: The use of genomic research has exploded in recent years. Various guidelines recommend disclosure of significant, clinically validated findings to participants. Continued debate in this area has led to calls for stakeholder involvement to inform policy. In particular, the attitudes of genomics researchers are salient yet relatively unexplored with respect to how the sharing of both targeted and incidental findings should be accomplished. Methods: All 107 researchers affiliated with two large-scale Genome Canada projects [Canadian Pediatric Cancer Genome Consortium (CPCGC) and the Finding of Rare Genes Canada Consortium (FORGE)] were surveyed using a mailed, validated 32-item questionnaire that had been pilot tested with genomics researchers. The survey was designed to cover a wide range of topics including attitudes of researchers to the return of incidental and targeted research results, the need for genetic counselling, responsibilities to participants over time, to child participants and to siblings of participants, and institutional ethics review. Two reminders were sent to non-respondents. Data were analyzed with descriptive statistics. Results: 74/107 (69%) responded. Most were between 41–55 yr of age (n=40, 54%) and had their most senior training inNorth America (n=67, 91%). The majority were experienced researchers (n=58, 78%) and felt comfortable in discussing genomic results with participants (n= 66, 89%). Respondents did not feel a strong responsibility to look for meaningful incidental results in the genomic data set they created (n=27, 37%). However, once potentially significant results were identified, researchers indicated that participants had a strong or very strong right to receive analytically validated genomic results irrespective of whether these results were incidental findings (n= 50, 68%) or primary targets of the research (n= 64, 87%). Most indicated that results with clinical utility that were actionable should be offered to participants (n=54, 73%) although some indicated that research results should not be returned under any circumstances (n=6, 8%). The majority felt that a research result should be confirmed in a clinical lab prior to return to participants (n=51, 69%). Most indicated that genetic counselling should be provided either almost always or frequently prior to genomic research participation (n=48, 64%). Respondents indicated that siblings of genomic research participants had a strong or very strong right to be informed of results (n=46, 62%), and this was especially true if an intervention to ameliorate the identified condition is feasible (n=56, 76%). A minority of researchers felt personal responsibility to ensure genomic research results obtained on a child of potential clinical utility were eventually communicated to him/her when the child became an adult (n=10, 14%). A slim majority felt the parents or health care provider should be responsible (n=38, 51%). Some researchers reported encountering incidental findings of clinical utility (n=25, 34%) and had offered them to participants. However, the minority reported that their institutional ethics review boards either always (n=10, 14%) or sometimes (n=24, 32%) required an offer of results. Only 16 (22%) indicated that their ethics board had a detailed process on how to do so. Conclusions: Researchers in general support the offer of return of targeted and incidental genomic research results to participants. A minority strongly oppose such action. There is typically a high degree of support for the offer of genomic research findings to siblings, especially if actionable. Given the new developments in genomics and resulting incidental findings, researchers describe little specific guidance about the process that should be followed in returning results to participants. Greater policy guidance would be of assistance in providing a consistent approach to the offer of incidental or targeted genomic research results. Acknowledgments: Funded by Genome Canada and the Canadian Institutes of Health Research. Disclosures: No relevant conflicts of interest to declare.

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The emerging field of polygenic risk scores and perspective for use in clinical care

Human Molecular Genetics ◽

10.1093/hmg/ddaa136 ◽

2020 ◽

Vol 29 (R2) ◽

pp. R165-R176

Author(s):

Tatiane Yanes ◽

Aideen M McInerney-Leo ◽

Matthew H Law ◽

Shelly Cummings

Keyword(s):

Genetic Testing ◽

Clinical Utility ◽

Clinical Care ◽

Polygenic Risk Score ◽

Genome Wide Association Studies ◽

Polygenic Risk ◽

Screening Programs ◽

Complex Disorders ◽

Genome Wide ◽

Monogenic Diseases

Abstract Genetic testing is used widely for diagnostic, carrier and predictive testing in monogenic diseases. Until recently, there were no genetic testing options available for multifactorial complex diseases like heart disease, diabetes and cancer. Genome-wide association studies (GWAS) have been invaluable in identifying single-nucleotide polymorphisms (SNPs) associated with increased or decreased risk for hundreds of complex disorders. For a given disease, SNPs can be combined to generate a cumulative estimation of risk known as a polygenic risk score (PRS). After years of research, PRSs are increasingly used in clinical settings. In this article, we will review the literature on how both genome-wide and restricted PRSs are developed and the relative merit of each. The validation and evaluation of PRSs will also be discussed, including the recognition that PRS validity is intrinsically linked to the methodological and analytical approach of the foundation GWAS together with the ethnic characteristics of that cohort. Specifically, population differences may affect imputation accuracy, risk magnitude and direction. Even as PRSs are being introduced into clinical practice, there is a push to combine them with clinical and demographic risk factors to develop a holistic disease risk. The existing evidence regarding the clinical utility of PRSs is considered across four different domains: informing population screening programs, guiding therapeutic interventions, refining risk for families at high risk, and facilitating diagnosis and predicting prognostic outcomes. The evidence for clinical utility in relation to five well-studied disorders is summarized. The potential ethical, legal and social implications are also highlighted.

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The clinical application of genome-wide sequencing for monogenic diseases in Canada: Position Statement of the Canadian College of Medical Geneticists

Journal of Medical Genetics ◽

10.1136/jmedgenet-2015-103144 ◽

2015 ◽

Vol 52 (7) ◽

pp. 431-437 ◽

Cited By ~ 102

Author(s):

Kym Boycott ◽

Taila Hartley ◽

Shelin Adam ◽

Francois Bernier ◽

Karen Chong ◽

...

Keyword(s):

Clinical Application ◽

Position Statement ◽

Genome Wide ◽

Monogenic Diseases

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Difficulties of Prenatal Genetic Counseling for a Subsequent Child in a Family With Multiple Genetic Variations

Frontiers in Genetics ◽

10.3389/fgene.2021.612100 ◽

2021 ◽

Vol 12 ◽

Author(s):

Ting-Xuan Huang ◽

Gwo-Chin Ma ◽

Ming Chen ◽

Wen-Fang Li ◽

Steven W. Shaw

Keyword(s):

Genetic Counseling ◽

De Novo ◽

Genetic Diagnosis ◽

Genetic Variations ◽

Epileptic Encephalopathy ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Prenatal Counseling ◽

Ethical Implications ◽

Genome Wide

Many parents with a disabled child caused by a genetic condition appreciate the option of prenatal genetic diagnosis to understand the chance of recurrence in a future pregnancy. Genome-wide tests, such as chromosomal microarray analysis and whole-exome sequencing, have been increasingly used for prenatal diagnosis, but prenatal counseling can be challenging due to the complexity of genomic data. This situation is further complicated by incidental findings of additional genetic variations in subsequent pregnancies. Here, we report the prenatal identification of a baby with a MECP2 missense variant and 15q11.2 microduplication in a family that has had a child with developmental and epileptic encephalopathy caused by a de novo KCNQ2 variant. An extended segregation analysis including extended relatives, in addition to the parents, was carried out to provide further information for genetic counseling. This case illustrates the challenges of prenatal counseling and highlights the need to understand the clinical and ethical implications of genome-wide tests.

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Clinical utility of comprehensive genomic profiling in central nervous system tumors of children and young adults

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab037 ◽

2021 ◽

Vol 3 (1) ◽

Author(s):

Jianling Ji ◽

Kristiyana Kaneva ◽

Matthew C Hiemenz ◽

Girish Dhall ◽

Tom Belle Davidson ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Clinical Utility ◽

Adolescent And Young Adult ◽

Cns Tumors ◽

Chromosomal Microarray ◽

Chromosomal Microarray Analysis ◽

Genomic Profiling ◽

Comprehensive Genomic Profiling ◽

Clinically Significant

Abstract Background Recent large-scale genomic studies have revealed a spectrum of genetic variants associated with specific subtypes of central nervous system (CNS) tumors. The aim of this study was to determine the clinical utility of comprehensive genomic profiling of pediatric, adolescent and young adult (AYA) CNS tumors in a prospective setting, including detection of DNA sequence variants, gene fusions, copy number alterations (CNAs), and loss of heterozygosity. Methods OncoKids, a comprehensive DNA- and RNA-based next-generation sequencing (NGS) panel, in conjunction with chromosomal microarray analysis (CMA) was employed to detect diagnostic, prognostic, and therapeutic markers. NGS was performed on 222 specimens from 212 patients. Clinical CMA data were analyzed in parallel for 66% (146/222) of cases. Results NGS demonstrated clinically significant alterations in 66% (147/222) of cases. Diagnostic markers were identified in 62% (138/222) of cases. Prognostic information and targetable genomic alterations were identified in 22% (49/222) and 18% (41/222) of cases, respectively. Diagnostic or prognostic CNAs were revealed by CMA in 69% (101/146) of cases. Importantly, clinically significant CNAs were detected in 57% (34/60) of cases with noncontributory NGS results. Germline cancer predisposition testing was indicated for 27% (57/212) of patients. Follow-up germline testing was performed for 20 patients which confirmed a germline pathogenic/likely pathogenic variant in 9 cases: TP53 (2), NF1 (2), SMARCB1 (1), NF2 (1), MSH6 (1), PMS2 (1), and a patient with 47,XXY Klinefelter syndrome. Conclusions Our results demonstrate the significant clinical utility of integrating genomic profiling into routine clinical testing for pediatric and AYA patients with CNS tumors.

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Towards Routine Implementation of Liquid Biopsies in Cancer Management: It Is Always Too Early, until Suddenly It Is Too Late

Diagnostics ◽

10.3390/diagnostics11010103 ◽

2021 ◽

Vol 11 (1) ◽

pp. 103

Author(s):

Maarten J. IJzerman ◽

Jasper de Boer ◽

Arun Azad ◽

Koen Degeling ◽

Joel Geoghegan ◽

...

Keyword(s):

Clinical Utility ◽

Clinical Laboratory ◽

Genomic Analysis ◽

Current Evidence ◽

Liquid Biopsies ◽

Blood Draw ◽

Minimum Quality Standards ◽

Cancer Management ◽

Alternative Funding ◽

And Performance

Blood-based liquid biopsies are considered a new and promising diagnostic and monitoring tool for cancer. As liquid biopsies only require a blood draw, they are non-invasive, potentially more rapid and assumed to be a less costly alternative to genomic analysis of tissue biopsies. A multi-disciplinary workshop (n = 98 registrations) was organized to discuss routine implementation of liquid biopsies in cancer management. Real-time polls were used to engage with experts’ about the current evidence of clinical utility and the barriers to implementation of liquid biopsies. Clinical, laboratory and health economics presentations were given to illustrate the opportunities and current levels of evidence, followed by three moderated break-out sessions to discuss applications. The workshop concluded that tumor-informed assays using next-generation sequencing (NGS) or PCR-based genotyping assays will most likely provide better clinical utility than tumor-agnostic assays, yet at a higher cost. For routine application, it will be essential to determine clinical utility, to define the minimum quality standards and performance of testing platforms and to ensure their use is integrated into current clinical workflows including how they complement tissue biopsies and imaging. Early health economic models may help identifying the most viable application of liquid biopsies. Alternative funding models for the translation of complex molecular diagnostics, such as liquid biopsies, may also be explored if clinical utility has been demonstrated and when their use is recommended in multi-disciplinary consensus guidelines.

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Clinical utility of brain stimulation modalities following traumatic brain injury: current evidence

Neuropsychiatric Disease and Treatment ◽

10.2147/ndt.s65816 ◽

2015 ◽

pp. 1573 ◽

Cited By ~ 6

Author(s):

Felipe Fregni ◽

Shasha Li ◽

Ana Zaninotto ◽

Iuri Santana Neville ◽

Wellingson Paiva ◽

...

Keyword(s):

Traumatic Brain Injury ◽

Brain Injury ◽

Brain Stimulation ◽

Clinical Utility ◽

Current Evidence

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Preimplantation Genetic Diagnosis—An Overview

Journal of Histochemistry & Cytochemistry ◽

10.1369/jhc.4b6395.2005 ◽

2005 ◽

Vol 53 (3) ◽

pp. 255-260 ◽

Cited By ~ 56

Author(s):

Caroline Mackie Ogilvie ◽

Peter R. Braude ◽

Paul N. Scriven

Keyword(s):

Preimplantation Genetic Diagnosis ◽

Genetic Diagnosis ◽

Sex Selection ◽

Hla Typing ◽

Success Rates ◽

Aneuploidy Screening ◽

Reciprocal Translocations ◽

Public Controversy ◽

Polar Bodies ◽

Monogenic Diseases

Since the early 1990s, preimplantation genetic diagnosis (PGD) has been expanding in scope and applications. Selection of female embryos to avoid X-linked disease was carried out first by polymerase chain reaction, then by fluorescence in situ hybridization (FISH), and an ever-increasing number of tests for monogenic diseases have been developed. Couples with chromosome rearrangements such as Robertsonian and reciprocal translocations form a large referral group for most PGD centers and present a special challenge, due to the large number of genetically unbalanced embryos generated by meiotic segregation. Early protocols used blastomeres biopsied from cleavage-stage embryos; testing of first and second polar bodies is now a routine alternative, and blastocyst biopsy can also be used. More recently, the technology has been harnessed to provide PGD-AS, or aneuploidy screening. FISH probes specific for chromosomes commonly found to be aneuploid in early pregnancy loss are used to test blastomeres for aneuploidy, with the aim of replacing euploid embryos and increasing pregnancy rates in groups of women who have poor IVF success rates. More recent application of PGD to areas such as HLA typing and social sex selection have stoked public controversy and concern, while provoking interesting ethical debates and keeping PGD firmly in the public eye.

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Information and genetic counselling for psychiatric risks in children with rare genomic disorders

10.1101/19007294 ◽

2019 ◽

Author(s):

Andrew Cuthbert ◽

Aimee Challenger ◽

Jeremy Hall ◽

Marianne BM van den Bree

Keyword(s):

Genetic Counselling ◽

Online Survey ◽

Genomic Medicine ◽

Genetic Diagnosis ◽

Single Nucleotide Variants ◽

Full Spectrum ◽

Face To Face ◽

Professional Information ◽

Genomic Disorders ◽

Psychiatric Manifestations

AbstractPurposeGenomic medicine has transformed the diagnosis of neurodevelopmental disorders. Evidence of increased psychiatric comorbidity associated with genomic copy number and single nucleotide variants (CNV and SNV) may not be fully considered when providing genetic counselling. We explored parents’ experiences of genetics services and how they obtained information concerning psychiatric manifestations.MethodsParents of children diagnosed with genomic variants completed an online survey exploring, (i) how they experienced the genetic diagnosis, and (ii) how they acquired information about psychiatric, developmental and physical manifestations.ResultsTwo-hundred and 86 respondents completed the survey. Thirty percent were unsatisfied with receiving genetic diagnoses. Satisfaction was predicted if communication was by geneticists (p = 0.004); provided face-to-face (p = 0.003); clearly explained (p < 0.001); and accompanied by support (p = 0.017). Parents obtained psychiatric information from non-professional sources more often than developmental (ϕ 0.26, p < 0.001) and physical manifestations (ϕ 0.21, p = 0.003), which mostly came from health professionals. Information from support organisations was more helpful than from geneticists (odds ratio [OR] 21.0, 95% CI 5.1 – 86.8, p < 0.001); paediatricians (OR 11.0, 1.4 – 85.2, p = 0.004); and internet sites (OR 15.5, 3.7 – 64.8, p < 0.001).ConclusionA paucity of professional information about psychiatric risks after genetic diagnosis may impede early diagnosis and intervention for children with high genotypic risks. Planned integration of genomic testing into mainstream services should include genetic counselling training to address the full spectrum of developmental, physical and psychiatric manifestations and timely provision of high-quality information.

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