|
1
|
Gaudillat L, Patay L, Sawka C, Baurand A, Nambot S, Level C, Laurent G, Eicher JC, Bertaux G, Eicher SF, Denis C, Carvallo S, Cazeneuve C, Janin A, Millat G, Peyron C, Thauvin-Robinet C, Charron P, Faivre L. Cardiogenetics and uncertainty: Evaluation of professional vulnerability in France. Eur J Med Genet 2025; 74:104999. [PMID: 39933637 DOI: 10.1016/j.ejmg.2025.104999] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2024] [Revised: 12/13/2024] [Accepted: 02/08/2025] [Indexed: 02/13/2025]
Abstract
Scientific advances in genomics are transforming healthcare and prevention. However, they also increase situations of uncertainty, which in turn increase vulnerability not only for patients and their families but also for professionals. Cardiogenetics plays a crucial role in preventing sudden death in young individuals, but it can pose complex challenges for healthcare teams. To study professionals' perspectives and experiences regarding cardiogenetics-related vulnerability, a national online survey was conducted in France to gather insight from professionals involved in the care pathway of individuals with cardiogenetic conditions. The survey targeted clinical geneticists, genetic counselors, cardiologists, nurses, and psychologists, in collaboration with the CARDIOGEN network. Out of 86 respondents, the majority (64%) reported experiencing vulnerability, which was not correlated with their profession, experience, or the organization of their clinics. Acknowledged vulnerabilities were mainly related to uncertainties regarding incomplete penetrance, variable expression, and genotype-phenotype disparities in cardiogenetics, exacerbated by the evolving interpretation of genetic data, due to the increased access to genomics. Additionally, the implications of these issues, particularly in cases of unexplained sudden deaths that necessitated genetic investigations and family follow up recommendations, raised further concerns. The reported vulnerabilities encompassed both the need for specialized knowledge and the structural complexities of teams combining skills in genetics and cardiology. In addition, the professionals' capacity to empathize can add a degree of vulnerability. Finally, it seems important to focus on how cardiogenetics teams are organized, particularly through close collaboration among genetics and cardiology units, which could help reduce this feeling of vulnerability.
Collapse
Affiliation(s)
- Lea Gaudillat
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France.
| | - Lea Patay
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Caroline Sawka
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Amandine Baurand
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France
| | - Sophie Nambot
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France
| | - Camille Level
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France
| | - Gabriel Laurent
- Departement de cardiologie, CHU Dijon Bourgogne, Dijon, France
| | | | | | | | - Charlotte Denis
- Departement de cardiologie, CHU Dijon Bourgogne, Dijon, France
| | - Sarah Carvallo
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France; Logiques de l'Agir (EA 2274) - MSHE (UAR 3124) Université de Franche Comté, France
| | - Cécile Cazeneuve
- UF Pathologies Cardiaques Héréditaires, Service de Biochimie, Hospices Civils de Lyon, Bron, France
| | - Alexandre Janin
- UF Pathologies Cardiaques Héréditaires, Service de Biochimie, Hospices Civils de Lyon, Bron, France
| | - Gilles Millat
- UF Pathologies Cardiaques Héréditaires, Service de Biochimie, Hospices Civils de Lyon, Bron, France
| | - Christine Peyron
- Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France; Laboratoire d'Economie de Dijon, Equipe Economie de la Santé, Université de Bourgogne, Dijon, France
| | - Christel Thauvin-Robinet
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France
| | - Philippe Charron
- Departement de génétique, Centre de Référence des maladies cardiaques héréditaires ou rares, APHP, Sorbonne Université, Inserm U1166, Hôpital Pitié-Salpêtrière, Paris, France
| | - Laurence Faivre
- Centre de Référence Anomalies du Développement et Syndromes Malformatifs Est, Hôpital d'Enfants, CHU Dijon Bourgogne, Dijon, France; Inserm UMR1231 GAD, Génétique des Anomalies du Développement, Université de Bourgogne, Dijon, France; Fédération Hospitalo-Universitaire Médecine Translationnelle et Anomalies du Développement, CHU Dijon Bourgogne, Dijon, France.
| |
Collapse
|
|
2
|
Elfatih A, Saad C, Mifsud B, Mbarek H. Analysis of 14,392 whole genomes reveals 3.5% of Qataris carry medically actionable variants. Eur J Hum Genet 2024; 32:1465-1473. [PMID: 39020067 PMCID: PMC11576737 DOI: 10.1038/s41431-024-01656-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Revised: 06/05/2024] [Accepted: 06/19/2024] [Indexed: 07/19/2024] Open
Abstract
Arabic populations are underrepresented in large genome projects; therefore, the frequency of clinically actionable variants among Arabs is largely unknown. Here, we investigated genetic variation in 14,392 whole genomes from the Qatar Genome Program (QGP) across the list of 78 actionable genes (v3.1) determined by the American College of Medical Genetics and Genomics (ACMG). Variants were categorized into one of the following groups: (1) Pathogenic (P), (2) Likely pathogenic (LP), and (3) Rare variants of uncertain significance with evidence of pathogenicity. For the classification, we used variant databases, effect predictors, and the disease-relevant phenotypes available for the cohort. Data on cardiovascular disease, cancer, and hypercholesterolemia allowed us to assess the disease-relevant phenotype association of rare missense variants. We identified 248 distinct variants in 50 ACMG genes that fulfilled our criteria to be included in one of the three groups affecting 1036 genotype-positive participants of the QGP cohort. The most frequent variants were in TTN, followed by RYR1 and ATP7B. The prevalence of reportable secondary findings was 3.5%. A further 46 heterozygous variants in six genes with an autosomal recessive mode of inheritance were detected in 200 individuals, accounting for an additional 1.4%. Altogether, they affect 5% of the population. Due to the high consanguinity rate in the QGP cohort (28% in spouses and 60% in parents), P and LP variants both in genes with dominant and recessive inheritance are important for developing better treatment options and preventive strategies in Qatar and the Arabic population of the Middle East.
Collapse
Affiliation(s)
- Amal Elfatih
- Hamad Bin Khalifa University, College of Health and Life Science, Genomics and Precision Medicine, Doha, Qatar
| | - Chadi Saad
- Qatar Genome Program, Qatar Foundation, Qatar Science and Technology Park, Innovation Center, Doha, Qatar
| | - Borbala Mifsud
- Hamad Bin Khalifa University, College of Health and Life Science, Genomics and Precision Medicine, Doha, Qatar.
- William Harvey Research Institute, Queen Mary University London, London, UK.
| | - Hamdi Mbarek
- Qatar Genome Program, Qatar Foundation, Qatar Science and Technology Park, Innovation Center, Doha, Qatar.
| |
Collapse
|
|
3
|
Viora-Dupont E, Robert F, Chassagne A, Pélissier A, Staraci S, Sanlaville D, Edery P, Lesca G, Putoux A, Pons L, Cadenes A, Baurand A, Sawka C, Bertolone G, Spetchian M, Yousfi M, Salvi D, Gautier E, Vitobello A, Denommé-Pichon AS, Bruel AL, Tran Mau-Them F, Faudet A, Keren B, Labalme A, Chatron N, Abel C, Dupuis-Girod S, Poisson A, Buratti J, Mignot C, Afenjar A, Whalen S, Charles P, Heide S, Mouthon L, Moutton S, Sorlin A, Nambot S, Briffaut AS, Asensio ML, Philippe C, Thauvin-Robinet C, Héron D, Rossi M, Meunier-Bellard N, Gargiulo M, Peyron C, Binquet C, Faivre L. Expectations, needs and mid-term outcomes in people accessing to secondary findings from ES: 1st French mixed study (FIND Study). Eur J Hum Genet 2024; 32:1166-1183. [PMID: 38802530 PMCID: PMC11368951 DOI: 10.1038/s41431-024-01616-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 03/01/2024] [Accepted: 04/17/2024] [Indexed: 05/29/2024] Open
Abstract
Generation and subsequently accessibility of secondary findings (SF) in diagnostic practice is a subject of debate around the world and particularly in Europe. The French FIND study has been set up to assess patient/parent expectations regarding SF from exome sequencing (ES) and to collect their real-life experience until 1 year after the delivery of results. 340 patients who had ES for undiagnosed developmental disorders were included in this multicenter mixed study (quantitative N = 340; qualitative N = 26). Three groups of actionable SF were rendered: predisposition to late-onset actionable diseases; genetic counseling; pharmacogenomics. Participants expressed strong interest in obtaining SF and a high satisfaction level when a SF is reported. The medical actionability of the SF reinforced parents' sense of taking action for their child and was seen as an opportunity. While we observed no serious psychological concerns, we showed that these results could have psychological consequences, in particular for late-onset actionable diseases SF, within families already dealing with rare diseases. This study shows that participants remain in favor of accessing SF despite the potential psychological, care, and lifestyle impacts, which are difficult to anticipate. The establishment of a management protocol, including the support of a multidisciplinary team, would be necessary if national policy allows the reporting of these data.
Collapse
Affiliation(s)
- Eléonore Viora-Dupont
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France.
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France.
| | - Françoise Robert
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- Clinical Psychology Lab., Psychopathology, Psychoanalysis (EA4056, ED 261), University of Paris, Sorbonne Paris City, Paris, France
| | - Aline Chassagne
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- Laboratory of Sociology and Anthropology (LaSA, EA3189), University of Burgundy-Franche-Comté, Besançon, France
| | - Aurore Pélissier
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- Laboratory of economy (LEDi), University of Burgundy, Dijon, France
| | - Stéphanie Staraci
- Genetics Department, Reference Center for Hereditary Cardiac Disorders, GH APHP, Paris, France
| | - Damien Sanlaville
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- Univ Lyon, Univ Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008, Lyon, France
| | - Patrick Edery
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- INSERM U1028, CNRS UMR5292, CRNL, GENDEV Team, University of Claude Bernard Lyon 1, Bron, France
| | - Gaetan Lesca
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- Univ Lyon, Univ Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008, Lyon, France
| | - Audrey Putoux
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- INSERM U1028, CNRS UMR5292, CRNL, GENDEV Team, University of Claude Bernard Lyon 1, Bron, France
| | - Linda Pons
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
| | - Amandine Cadenes
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
| | - Amandine Baurand
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Caroline Sawka
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Geoffrey Bertolone
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Myrtille Spetchian
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Meriem Yousfi
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Dominique Salvi
- Laboratory of economy (LEDi), University of Burgundy, Dijon, France
| | - Elodie Gautier
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Antonio Vitobello
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
| | | | - Ange-Line Bruel
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
| | | | - Anne Faudet
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Boris Keren
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Audrey Labalme
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
| | - Nicolas Chatron
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- Univ Lyon, Univ Lyon 1, CNRS, INSERM, Physiopathologie et Génétique du Neurone et du Muscle, UMR5261, U1315, Institut NeuroMyoGène, 69008, Lyon, France
| | - Carine Abel
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
| | - Sophie Dupuis-Girod
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
| | - Alice Poisson
- Reference Center for Rare Disorders with psychiatric expression C.H. Le Vinatier, Bron, France
- Equipe de recherche AESIO santé, unité de Sant Etienne, Clinique médico chirurgicale mutualiste, Saint Etienne, France
| | - Julien Buratti
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Cyril Mignot
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Alexandra Afenjar
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Sandra Whalen
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Perrine Charles
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Solveig Heide
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Linda Mouthon
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Sébastien Moutton
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Arthur Sorlin
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Sophie Nambot
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France
| | - Anne-Sophie Briffaut
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- CHU Dijon Bourgogne, INSERM, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Marie-Laure Asensio
- CHU Dijon Bourgogne, INSERM, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | | | - Christel Thauvin-Robinet
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- Genetics Department, Reference Center for Intellectual Disabilities, University Hospital, Dijon, France
| | - Delphine Héron
- Genetics Department, Reference Center for Developmental Disorders, GH APHP, Paris, France
| | - Massimiliano Rossi
- Genetics Department, Reference Center for Developmental Disorders, HCL, Bron, France
- INSERM U1028, CNRS UMR5292, CRNL, GENDEV Team, University of Claude Bernard Lyon 1, Bron, France
| | - Nicolas Meunier-Bellard
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- CHU Dijon Bourgogne, INSERM, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Marcela Gargiulo
- Clinical Psychology Lab., Psychopathology, Psychoanalysis (EA4056, ED 261), University of Paris, Sorbonne Paris City, Paris, France
- Institute of myology, GH APHP, Paris, France
| | - Christine Peyron
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- Laboratory of economy (LEDi), University of Burgundy, Dijon, France
| | - Christine Binquet
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France
- CHU Dijon Bourgogne, INSERM, Université de Bourgogne, CIC 1432, Module Épidémiologie Clinique, Dijon, France
| | - Laurence Faivre
- FHU TRANSLAD, GAD INSERM UMR 1231, University of Burgundy, Dijon, France.
- Genetics Department, Reference Center for Developmental Disorders, University Hospital, Dijon, France.
| |
Collapse
|
|
4
|
Friedman JM, Bombard Y, Carleton B, Issa AM, Knoppers B, Plon SE, Rahimzadeh V, Relling MV, Williams MS, van Karnebeek C, Vears D, Cornel MC. Should secondary pharmacogenomic variants be actively screened and reported when diagnostic genome-wide sequencing is performed in a child? Genet Med 2024; 26:101033. [PMID: 38007624 DOI: 10.1016/j.gim.2023.101033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2023] [Revised: 11/14/2023] [Accepted: 11/19/2023] [Indexed: 11/27/2023] Open
Abstract
This white paper was prepared by the Global Alliance for Genomics and Health Regulatory and Ethics Work Stream's Pediatric Task Team to review and provide perspective with respect to ethical, legal, and social issues regarding the return of secondary pharmacogenomic variants in children who have a serious disease or developmental disorder and are undergoing exome or genome sequencing to identify a genetic cause of their condition. We discuss actively searching for and reporting pharmacogenetic/genomic variants in pediatric patients, different methods of returning secondary pharmacogenomic findings to the patient/parents and/or treating clinicians, maintaining these data in the patient's health record over time, decision supports to assist using pharmacogenetic results in future treatment decisions, and sharing information in public databases to improve the clinical interpretation of pharmacogenetic variants identified in other children. We conclude by presenting a series of points to consider for clinicians and policymakers regarding whether, and under what circumstances, routine screening and return of pharmacogenomic variants unrelated to the indications for testing is appropriate in children who are undergoing genome-wide sequencing to assist in the diagnosis of a suspected genetic disease.
Collapse
Affiliation(s)
- Jan M Friedman
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada.
| | - Yvonne Bombard
- Genomics Health Services Research Program, St. Michael's Hospital, Unity Health Toronto, Toronto, Ontario, Canada; Institute of Health Policy, Management and Evaluation, University of Toronto, Toronto, Ontario, Canada
| | - Bruce Carleton
- Department of Medical Genetics, University of British Columbia, Vancouver, British Columbia, Canada; Division of Translational Therapeutics, Department of Pediatrics, University of British Columbia, Vancouver, British Columbia, Canada; Pharmaceutical Outcomes Programme, British Columbia Children's Hospital, Vancouver, British Columbia, Canada
| | - Amalia M Issa
- Personalized Precision Medicine & Targeted Therapeutics, Springfield, MA; Health Policy, University of the Sciences, Philadelphia, PA; Pharmaceutical Sciences, University of the Sciences, Philadelphia, PA; Family Medicine, McGill University, Montreal, Quebec, Canada
| | - Bartha Knoppers
- Centre of Genomics and Policy, Faculty of Medicine and Health Sciences, McGill University, Montreal, Quebec, Canada
| | - Sharon E Plon
- Department of Pediatrics, Texas Children's Cancer and Hematology Center, Baylor College of Medicine, Houston, TX; Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX
| | - Vasiliki Rahimzadeh
- Center for Medical Ethics and Health Policy, Baylor College of Medicine, Houston, TX
| | - Mary V Relling
- Department of Pharmacy and Pharmaceutical Sciences, St. Jude Children's Research Hospital, Memphis, TN
| | | | - Clara van Karnebeek
- Emma Center for Personalized Medicine, Amsterdam UMC, Amsterdam, The Netherlands; Departments of Pediatrics and Human Genetics, Emma Children's Hospital, Amsterdam University Medical Centers, Amsterdam, The Netherlands; United for Metabolic Diseases, The Netherlands; Radboud Center for Mitochondrial and Metabolic Medicine, Department of Pediatrics, Amalia Children's Hospital, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Danya Vears
- University of Melbourne, Carlton, Melbourne, Australia; Biomedical Ethics Research Group, Murdoch Children's Research Institute, Parkville, Victoria, Australia
| | - Martina C Cornel
- Department of Human Genetics and Amsterdam Public Health Research Institute, Amsterdam University Medical Centres, Amsterdam, The Netherlands
| |
Collapse
|
|
5
|
Chipoulet E, Collet G, Couderc B. [The role of physicians in patient and family adherence to genetic testing]. Bull Cancer 2023; 110:1002-1014. [PMID: 37532643 DOI: 10.1016/j.bulcan.2023.05.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 05/05/2023] [Accepted: 05/12/2023] [Indexed: 08/04/2023]
Abstract
INTRODUCTION More and more French cancer patients are offered by their physicians having their genetic characteristics analyzed (diagnosis, adaptation of treatment plans, etc.). In oncology, considering the development of personalized medicine, these analyses are commonplace. Analyses of germline (hereditary) genetic characteristics require information from patients who must sign an informed consent (article 16.10 of the Civil Code and articles L. 1131-3 and L. 1122-1-1 of the Public Health Code). However, prescribing physicians are rarely geneticists and have little training in genetics. Patients report that few are able to answer their questions and often sign a consent that is not truly informed. METHODS To identify the genetic knowledge and training needs of prescribers, we conducted an online survey of physicians prescribing genetic testing in oncology between January and March 2020. The survey consisted of 17 closed questions and 3 open questions. RESULTS We obtained 35 usable questionnaires which show that 50% of the prescribing physicians questioned lack knowledge of genetics, but do not express a need for training. They were interested in the provision of a digital teaching aid for patients. DISCUSSION We have therefore made a film for patients, available in free access, which aims to shed light on the analysis of genetic characteristics. The film helps physicians to explain the offered analyses and their consequences (https://youtu.be/5lWUSsteavs).
Collapse
Affiliation(s)
| | | | - Bettina Couderc
- IUCT-Oncopole, Toulouse, France; Université Toulouse 3, UMR 1295 Inserm, Toulouse, France.
| |
Collapse
|
|
6
|
McGurk KA, Zhang X, Theotokis P, Thomson K, Harper A, Buchan RJ, Mazaika E, Ormondroyd E, Wright WT, Macaya D, Pua CJ, Funke B, MacArthur DG, Prasad SK, Cook SA, Allouba M, Aguib Y, Yacoub MH, O'Regan DP, Barton PJR, Watkins H, Bottolo L, Ware JS. The penetrance of rare variants in cardiomyopathy-associated genes: A cross-sectional approach to estimating penetrance for secondary findings. Am J Hum Genet 2023; 110:1482-1495. [PMID: 37652022 PMCID: PMC10502871 DOI: 10.1016/j.ajhg.2023.08.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 07/21/2023] [Accepted: 08/04/2023] [Indexed: 09/02/2023] Open
Abstract
Understanding the penetrance of pathogenic variants identified as secondary findings (SFs) is of paramount importance with the growing availability of genetic testing. We estimated penetrance through large-scale analyses of individuals referred for diagnostic sequencing for hypertrophic cardiomyopathy (HCM; 10,400 affected individuals, 1,332 variants) and dilated cardiomyopathy (DCM; 2,564 affected individuals, 663 variants), using a cross-sectional approach comparing allele frequencies against reference populations (293,226 participants from UK Biobank and gnomAD). We generated updated prevalence estimates for HCM (1:543) and DCM (1:220). In aggregate, the penetrance by late adulthood of rare, pathogenic variants (23% for HCM, 35% for DCM) and likely pathogenic variants (7% for HCM, 10% for DCM) was substantial for dominant cardiomyopathy (CM). Penetrance was significantly higher for variant subgroups annotated as loss of function or ultra-rare and for males compared to females for variants in HCM-associated genes. We estimated variant-specific penetrance for 316 recurrent variants most likely to be identified as SFs (found in 51% of HCM- and 17% of DCM-affected individuals). 49 variants were observed at least ten times (14% of affected individuals) in HCM-associated genes. Median penetrance was 14.6% (±14.4% SD). We explore estimates of penetrance by age, sex, and ancestry and simulate the impact of including future cohorts. This dataset reports penetrance of individual variants at scale and will inform the management of individuals undergoing genetic screening for SFs. While most variants had low penetrance and the costs and harms of screening are unclear, some individuals with highly penetrant variants may benefit from SFs.
Collapse
Affiliation(s)
- Kathryn A McGurk
- National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Xiaolei Zhang
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Pantazis Theotokis
- National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Kate Thomson
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Andrew Harper
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Rachel J Buchan
- National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Erica Mazaika
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Elizabeth Ormondroyd
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - William T Wright
- Northern Ireland Regional Genetics Centre, Belfast Health and Social Care Trust, Belfast City Hospital, Belfast, Northern Ireland, UK
| | | | - Chee Jian Pua
- National Heart Research Institute Singapore and Duke-National University of Singapore, Singapore, Singapore
| | - Birgit Funke
- Laboratory for Molecular Medicine, Partners Healthcare Center for Personalized Genetic Medicine, Boston, MA, USA
| | - Daniel G MacArthur
- Centre for Population Genomics, Garvan Institute of Medical Research and UNSW, Sydney, NSW, Australia; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, VIC, Australia
| | - Sanjay K Prasad
- National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Stuart A Cook
- MRC London Institute of Medical Sciences, Imperial College London, London, UK; National Heart Research Institute Singapore and Duke-National University of Singapore, Singapore, Singapore
| | - Mona Allouba
- National Heart and Lung Institute, Imperial College London, London, UK; Aswan Heart Centre, Aswan, Egypt
| | - Yasmine Aguib
- National Heart and Lung Institute, Imperial College London, London, UK; Aswan Heart Centre, Aswan, Egypt
| | - Magdi H Yacoub
- National Heart and Lung Institute, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK; Aswan Heart Centre, Aswan, Egypt
| | - Declan P O'Regan
- MRC London Institute of Medical Sciences, Imperial College London, London, UK
| | - Paul J R Barton
- National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK
| | - Hugh Watkins
- Division of Cardiovascular Medicine, Radcliffe Department of Medicine and the Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK
| | - Leonardo Bottolo
- Department of Medical Genetics, University of Cambridge, Cambridge, UK; The Alan Turing Institute, London, UK; MRC Biostatistics Unit, University of Cambridge, Cambridge, UK
| | - James S Ware
- National Heart and Lung Institute, Imperial College London, London, UK; MRC London Institute of Medical Sciences, Imperial College London, London, UK; Royal Brompton & Harefield Hospitals, Guy's and St. Thomas' NHS Foundation Trust, London, UK.
| |
Collapse
|
|
7
|
Mazel B, Bertolone G, Baurand A, Cosset E, Sawka C, Robert M, Gautier E, Lançon A, Réda M, Favier L, Dérangère V, Richard C, Binquet C, Boidot R, Goussot V, Albuisson J, Ghiringhelli F, Faivre L, Nambot S. Advancing precision oncology through systematic germline and tumor genetic analysis: The oncogenetic point of view on findings from a prospective multicenter clinical trial of 666 patients. Cancer Med 2023; 12:18786-18796. [PMID: 37694493 PMCID: PMC10557826 DOI: 10.1002/cam4.6498] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 08/07/2023] [Accepted: 08/25/2023] [Indexed: 09/12/2023] Open
Abstract
INTRODUCTION With the emergence of targeted therapies, there is a need to accurately identify more tumor biomarkers. The EXOMA trial was designed to offer tumor and germline exome sequencing (ES) to patients with solid malignant tumors and facing therapeutic failure. As hereditary cancer predispositions could be identified, with genetic counseling and health management implications, a genetic consultation was systematically established. This design needs to be discussed as genetic human resources are limited and indication of theranostic tests will increase. METHODS Genetic counseling was conducted within 15 days following inclusion in the study for patients recruited between December 2015 and July 2019. In silico analyses from theranostic ES were limited to 317 genes involved in oncogenesis, from both tumor and blood DNA. RESULTS Six hundred and sixty six patients had a genetic consultation before ES. In 65/666 patients, 66 germline pathogenic or likely pathogenic (P/LP) variants were identified in 16 actionable genes and seven non-actionable genes according to French guidelines. 24/65 patients had previously received genetic analysis for diagnostic purposes, and for 17 of them, a P/LP variant had already been identified. Among the 48/65 remaining cases for which the EXOMA protocol revealed a previously unknown P/LP variant, only 19 met the criteria for genetic testing for inherited cancer risk after familial survey. These criteria had not been identified by the oncologist in 10 cases. In 21/65 cases, the variant was considered incidental. DISCUSSION In 7.4% of patients, an undiagnosed hereditary genetic predisposition was identified, whether or not related to the clinical presentation, and germline analysis impacted oncological management for only 6.3% of the cohort. This low percentage should be weighed against the burden of systematic genetic consultation and urgent circuits. Information or training tools to form oncologists to the prescription of germline genetic analyses should be explored, as well as information supports and patient preferences.
Collapse
Affiliation(s)
- Benoit Mazel
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- INSERM UMR 1231 GAD, Génétique des Anomalies du Développement, Université Bourgogne Franche‐ComtéDijonFrance
| | - Geoffrey Bertolone
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Amandine Baurand
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Elodie Cosset
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Caroline Sawka
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Marion Robert
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Elodie Gautier
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
| | - Allan Lançon
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Manon Réda
- Département d'Oncologie MédicaleCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
- Plateforme de Transfert en Biologie CancérologiqueCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Laure Favier
- Département d'Oncologie MédicaleCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
- Plateforme de Transfert en Biologie CancérologiqueCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Valentin Dérangère
- Plateforme de Transfert en Biologie CancérologiqueCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Corentin Richard
- INSERM UMR 1231 GIMI, Genomic and Immunotherapy Medical Institute, Université Bourgogne Franche‐ComtéDijonFrance
| | - Christine Binquet
- INSERM, CIC1432, Module Epidémiologie Clinique, Dijon, France; Centre Hospitalier Universitaire Dijon‐Bourgogne, Centre d'Investigation Clinique, module Epidémiologie clinique/essais cliniquesDijonFrance
| | - Romain Boidot
- Unité de Biologie MoléculaireCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
- Institut de Chimie Moléculaire de l'Université de Bourgogne, UMR CNRS 6302DijonFrance
| | - Vincent Goussot
- INSERM UMR 1231 GIMI, Genomic and Immunotherapy Medical Institute, Université Bourgogne Franche‐ComtéDijonFrance
- Unité de Biologie MoléculaireCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - Juliette Albuisson
- INSERM UMR 1231 GIMI, Genomic and Immunotherapy Medical Institute, Université Bourgogne Franche‐ComtéDijonFrance
- Unité de Biologie MoléculaireCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
| | - François Ghiringhelli
- Département d'Oncologie MédicaleCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
- Plateforme de Transfert en Biologie CancérologiqueCentre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
- INSERM UMR 1231 GIMI, Genomic and Immunotherapy Medical Institute, Université Bourgogne Franche‐ComtéDijonFrance
| | - Laurence Faivre
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- INSERM UMR 1231 GAD, Génétique des Anomalies du Développement, Université Bourgogne Franche‐ComtéDijonFrance
- INSERM UMR 1231 GIMI, Genomic and Immunotherapy Medical Institute, Université Bourgogne Franche‐ComtéDijonFrance
| | - Sophie Nambot
- Centre de Génétique, FHU‐TRANSLAD, Centre Hospitalier Universitaire Dijon‐BourgogneDijonFrance
- INSERM UMR 1231 GAD, Génétique des Anomalies du Développement, Université Bourgogne Franche‐ComtéDijonFrance
- Unité d'Oncogénétique, Centre de Lutte Contre le Cancer Georges François Leclerc—UNICANCERDijonFrance
- INSERM UMR 1231 GIMI, Genomic and Immunotherapy Medical Institute, Université Bourgogne Franche‐ComtéDijonFrance
| |
Collapse
|
|
8
|
Crooks KR, Farwell Hagman KD, Mandelker D, Santani A, Schmidt RJ, Temple-Smolkin RL, Lincoln SE. Recommendations for Next-Generation Sequencing Germline Variant Confirmation: A Joint Report of the Association for Molecular Pathology and National Society of Genetic Counselors. J Mol Diagn 2023; 25:411-427. [PMID: 37207865 DOI: 10.1016/j.jmoldx.2023.03.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2022] [Revised: 02/27/2023] [Accepted: 03/30/2023] [Indexed: 05/21/2023] Open
Abstract
Clinical laboratory implementation of next-generation sequencing (NGS)-based constitutional genetic testing has been rapid and widespread. In the absence of widely adopted comprehensive guidance, there remains substantial variability among laboratories in the practice of NGS. One issue of sustained discussion in the field is whether and to what extent orthogonal confirmation of genetic variants identified by NGS is necessary or helpful. The Association for Molecular Pathology Clinical Practice Committee convened the NGS Germline Variant Confirmation Working Group to assess current evidence regarding orthogonal confirmation and to establish recommendations for standardizing orthogonal confirmation practices to support quality patient care. On the basis of the results of a survey of the literature, a survey of laboratory practices, and subject expert matter consensus, eight recommendations are presented, providing a common framework for clinical laboratory professionals to develop or refine individualized laboratory policies and procedures regarding orthogonal confirmation of germline variants detected by NGS.
Collapse
Affiliation(s)
- Kristy R Crooks
- NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
| | - Kelly D Farwell Hagman
- NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Clinical Diagnostics, Ambry Genetics, Aliso Viejo, California
| | - Diana Mandelker
- NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Avni Santani
- NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; LetsGetChecked, PrivaPath Diagnostics, Dublin, Ireland; Veritas Genetics, Danvers, Massachusetts
| | - Ryan J Schmidt
- NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, California; Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California
| | | | - Stephen E Lincoln
- NGS Germline Variant Confirmation Working Group of the Clinical Practice Committee, Association for Molecular Pathology, Rockville, Maryland; InVitae, Bethesda, Maryland
| |
Collapse
|
|
9
|
Codina-Solà M, Trujillano L, Abulí A, Rovira-Moreno E, Muñoz-Cabello P, Campos B, Fernández-Álvarez P, Palau D, Carrasco E, Valenzuela I, Cueto-González AM, Lasa-Aranzasti A, Limeres J, Leno-Colorado J, Costa-Roger M, Moles-Fernández A, Balmaña J, Díez O, Cuscó I, Garcia-Arumí E, Tizzano EF. An spanish study of secondary findings in families affected with mendelian disorders: choices, prevalence and family history. Eur J Hum Genet 2023; 31:223-230. [PMID: 36446894 PMCID: PMC9905470 DOI: 10.1038/s41431-022-01240-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Revised: 11/02/2022] [Accepted: 11/08/2022] [Indexed: 12/02/2022] Open
Abstract
Clinical exome sequencing has the potential to identify pathogenic variants unrelated to the purpose of the study (secondary findings, SFs). Data describing actual choices of SFs in participants in a clinical setting and factors influencing their decision are virtually non-existant in Europe. In this work, we report the acceptance rate of SFs, calculate their prevalence and study factors associated with the decision in a cohort of patients affected with a rare genetic disorder in a Spanish Hospital. Finally, we re-examine the presence of previously non reported family history in positive cases. We retrospectively reviewed informed consent choices and SF results from 824 unrelated probands affected with rare genetic disorders who underwent whole-genome or exome sequencing. Ninety percent of families (740/824) affected with rare disorders wished to be informed of SFs. Declining SFs was associated with a prenatal setting (30% vs. 8.7%, p = 0.025), consanguinity (19% vs. 8.7%, p = 0.013), male gender (10.6% vs. 1.5%, p = 0.00865) and the proband being a minor (10.6% vs. 1.5%, p = 0.014). Overall, 27 pathogenic or likely pathogenic variants were identified in 27 individuals, with an SF prevalence of 3.6%. Disclosure of SFs increased the percentage of positive family histories and resulted in early diagnosis or changes in the management of 10 individuals from five families. We show that the acceptance of SFs in Spain is high and the disclosure of SFs leads to a clinically meaningful change in the medical management of individuals.
Collapse
Affiliation(s)
- Marta Codina-Solà
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain.
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain.
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain.
| | - Laura Trujillano
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
| | - Anna Abulí
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
| | - Eulàlia Rovira-Moreno
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
| | - Patricia Muñoz-Cabello
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Berta Campos
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Paula Fernández-Álvarez
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
| | - Dolors Palau
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Estela Carrasco
- Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Irene Valenzuela
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
| | - Anna Maria Cueto-González
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Amaia Lasa-Aranzasti
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
| | - Javier Limeres
- European Reference Networks for rare, low prevalence and complex diseases of the heart (ERN GUARD-Heart), Barcelona, Spain
- Unidad de Cardiopatías Familiares, Servicio de Cardiología, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Centre for Biomedical Network Research on Cardiovascular Diseases (CIBERCV), Madrid, Spain
| | - Jordi Leno-Colorado
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Mar Costa-Roger
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Alejandro Moles-Fernández
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Judith Balmaña
- Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, Barcelona, Spain
- Medical Oncology Department, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Orland Díez
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Hereditary Cancer Genetics Group, Vall d'Hebron Institute of Oncology (VHIO), Vall d'Hebron Barcelona Hospital Campus, Hospital Universitari Vall d'Hebron, Barcelona, Spain
| | - Ivon Cuscó
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
- Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
- Department of Genetics, Hospital Sant Pau, Barcelona, Spain
| | - Elena Garcia-Arumí
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
- Instituto de Salud Carlos III, Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain
- Research Group on Neuromuscular and Mitochondrial Disorders, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
| | - Eduardo Fidel Tizzano
- Medicine Genetics Group, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- Department of Clinical and Molecular Genetics, Vall d'Hebron Barcelona Hospital Campus, Vall d'Hebron Hospital Universitari, Barcelona, Spain
- European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability ERN-ITHACA, Barcelona, Spain
| |
Collapse
|
|
10
|
Parenti I, Leitão E, Kuechler A, Villard L, Goizet C, Courdier C, Bayat A, Rossi A, Julia S, Bruel AL, Tran Mau-Them F, Nambot S, Lehalle D, Willems M, Lespinasse J, Ghoumid J, Caumes R, Smol T, El Chehadeh S, Schaefer E, Abi-Warde MT, Keren B, Afenjar A, Tabet AC, Levy J, Maruani A, Aledo-Serrano Á, Garming W, Milleret-Pignot C, Chassevent A, Koopmans M, Verbeek NE, Person R, Belles R, Bellus G, Salbert BA, Kaiser FJ, Mazzola L, Convers P, Perrin L, Piton A, Wiegand G, Accogli A, Brancati F, Benfenati F, Chatron N, Lewis-Smith D, Thomas RH, Zara F, Striano P, Lesca G, Depienne C. The different clinical facets of SYN1-related neurodevelopmental disorders. Front Cell Dev Biol 2022; 10:1019715. [PMID: 36568968 PMCID: PMC9773998 DOI: 10.3389/fcell.2022.1019715] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2022] [Accepted: 10/20/2022] [Indexed: 12/13/2022] Open
Abstract
Synapsin-I (SYN1) is a presynaptic phosphoprotein crucial for synaptogenesis and synaptic plasticity. Pathogenic SYN1 variants are associated with variable X-linked neurodevelopmental disorders mainly affecting males. In this study, we expand on the clinical and molecular spectrum of the SYN1-related neurodevelopmental disorders by describing 31 novel individuals harboring 22 different SYN1 variants. We analyzed newly identified as well as previously reported individuals in order to define the frequency of key features associated with these disorders. Specifically, behavioral disturbances such as autism spectrum disorder or attention deficit hyperactivity disorder are observed in 91% of the individuals, epilepsy in 82%, intellectual disability in 77%, and developmental delay in 70%. Seizure types mainly include tonic-clonic or focal seizures with impaired awareness. The presence of reflex seizures is one of the most representative clinical manifestations related to SYN1. In more than half of the cases, seizures are triggered by contact with water, but other triggers are also frequently reported, including rubbing with a towel, fever, toothbrushing, fingernail clipping, falling asleep, and watching others showering or bathing. We additionally describe hyperpnea, emotion, lighting, using a stroboscope, digestive troubles, and defecation as possible triggers in individuals with SYN1 variants. The molecular spectrum of SYN1 variants is broad and encompasses truncating variants (frameshift, nonsense, splicing and start-loss variants) as well as non-truncating variants (missense substitutions and in-frame duplications). Genotype-phenotype correlation revealed that epileptic phenotypes are enriched in individuals with truncating variants. Furthermore, we could show for the first time that individuals with early seizures onset tend to present with severe-to-profound intellectual disability, hence highlighting the existence of an association between early seizure onset and more severe impairment of cognitive functions. Altogether, we present a detailed clinical description of the largest series of individuals with SYN1 variants reported so far and provide the first genotype-phenotype correlations for this gene. A timely molecular diagnosis and genetic counseling are cardinal for appropriate patient management and treatment.
Collapse
Affiliation(s)
- Ilaria Parenti
- Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Elsa Leitão
- Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Alma Kuechler
- Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Laurent Villard
- INSERM, MMG, Faculté de Médecine, Aix-Marseille University, Marseille, France
- Département de Génétique Médicale, APHM, Hôpital d'Enfants de La Timone, Marseille, France
| | - Cyril Goizet
- Service de Génétique Médicale, Bordeaux, France
- Centre de Référence Maladies Rares Neurogénétique, Service de Génétique Médicale, Bordeaux, France
- NRGEN Team, INCIA, CNRS UMR 5287, University of Bordeaux, Bordeaux, France
| | - Cécile Courdier
- Service de Génétique Médicale, Bordeaux, France
- Centre de Référence Maladies Rares Neurogénétique, Service de Génétique Médicale, Bordeaux, France
- NRGEN Team, INCIA, CNRS UMR 5287, University of Bordeaux, Bordeaux, France
| | - Allan Bayat
- Institute for Regional Health Services, University of Southern Denmark, Odense, Denmark
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark
- Department of Drug Design and Pharmacology, University of Copenhagen, Copenhagen, Denmark
| | - Alessandra Rossi
- Department of Epilepsy Genetics and Personalized Medicine, Danish Epilepsy Center, Dianalund, Denmark
- Pediatric Clinic, IRCCS Policlinico San Matteo Foundation, University of Pavia, Pavia, Italy
| | - Sophie Julia
- Service de Génétique Médicale, Pôle de Biologie, CHU de Toulouse - Hôpital Purpan, Toulouse, France
| | - Ange-Line Bruel
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
- UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
| | - Frédéric Tran Mau-Them
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
- UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
| | - Sophie Nambot
- UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
| | - Daphné Lehalle
- Unité Fonctionnelle Innovation en Diagnostic Génomique des Maladies Rares, FHU-TRANSLAD, CHU Dijon Bourgogne, Dijon, France
- UMR1231 GAD, Inserm - Université Bourgogne-Franche Comté, Dijon, France
| | - Marjolaine Willems
- Department of Medical Genetics, Rare diseases and Personalized Medicine, CHU Montpellier, University of Montpellier, Montpellier, France
- Inserm U1298, INM, CHU Montpellier, University of Montpellier, Montpellier, France
| | - James Lespinasse
- Service de Cytogenetique, Centre Hospitalier de Chambéry, Chambéry, France
| | - Jamal Ghoumid
- Univ. Lille, ULR7364 RADEME, Lille, France
- CHU Lille, Clinique de Génétique, Guy Fontaine, Lille, France
| | - Roseline Caumes
- Univ. Lille, ULR7364 RADEME, Lille, France
- CHU Lille, Clinique de Génétique, Guy Fontaine, Lille, France
| | - Thomas Smol
- Univ. Lille, ULR7364 RADEME, Lille, France
- CHU Lille, Institut de Génétique Médicale, Lille, France
| | - Salima El Chehadeh
- Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France
| | - Elise Schaefer
- Service de Génétique Médicale, Institut de Génétique Médicale d'Alsace (IGMA), Hôpitaux Universitaires de Strasbourg, Hôpital de Hautepierre, Strasbourg, France
| | | | - Boris Keren
- APHP, Département de Génétique, UF de Génomique du Développement, Département de Génétique, Groupe Hospitalier Pitié-Salpêtrière, Sorbonne Université, Paris, France
| | - Alexandra Afenjar
- Département de Génétique, Centre de Référence déficiences Intellectuelles de Causes Rares, APHP, Hôpital Armand Trousseau, Sorbonne Université, Paris, France
| | | | - Jonathan Levy
- APHP, Département de Génétique, Hôpital Robert-Debré, Paris, France
| | - Anna Maruani
- Department of Child and Adolescent Psychiatry, Robert Debré Hospital, APHP, Paris, France
| | - Ángel Aledo-Serrano
- Epilepsy and Neurogenetics Program, Neurology Department, Ruber Internacional Hospital, Madrid, Spain
| | - Waltraud Garming
- Sozialpädiatrisches Zentrum, Kinder-und Jugendklinik Gelsenkirchen, Gelsenkirchen, Germany
| | | | - Anna Chassevent
- Department of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, United States
| | - Marije Koopmans
- Department of Genetics, Utrecht University Medical Center, Utrecht, Netherlands
| | - Nienke E. Verbeek
- Department of Genetics, Utrecht University Medical Center, Utrecht, Netherlands
| | | | - Rebecca Belles
- Medical Genetics, Geisinger Medical Center, Danville, PA, United States
| | - Gary Bellus
- Medical Genetics, Geisinger Medical Center, Danville, PA, United States
| | - Bonnie A. Salbert
- Medical Genetics, Geisinger Medical Center, Danville, PA, United States
| | - Frank J. Kaiser
- Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- Essener Zentrum für Seltene Erkrankungen (EZSE), Universitätsklinikum Essen, Essen, Germany
| | - Laure Mazzola
- Department of Neurology, University Hospital, Lyon Neuroscience Research Center (CRNL), INSERM U1028, CNRS UMR5292, Lyon, France
- Department of Neurology, University Hospital, Saint-Etienne, France
| | - Philippe Convers
- Department of Neurology, University Hospital, Lyon Neuroscience Research Center (CRNL), INSERM U1028, CNRS UMR5292, Lyon, France
- Department of Neurology, University Hospital, Saint-Etienne, France
| | - Laurine Perrin
- Department of Paediatric Physical Medicine and Rehabilitation, CHU Saint-Étienne, Hôpital Bellevue, Rhône-Alpes Reference Centre for Neuromuscular Diseases, Saint-Étienne, France
| | - Amélie Piton
- Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch, France
- Centre National de la Recherche Scientifique, UMR7104, Illkirch, France
- Institut National de la Santé et de la Recherche Médicale, U964, Illkirch, France
- Université de Strasbourg, Illkirch, France
| | - Gert Wiegand
- Division of Pediatric Neurology, Department of Pediatrics, Asklepios Klinik Nord-Heidberg, Hamburg, Germany
- Department of Pediatric and Adolescent Medicine II (Neuropediatrics, Social Pediatrics), University Medical Centre Schleswig-Holstein, Kiel, Germany
| | - Andrea Accogli
- Department of Specialized Medicine, Division of Medical Genetics, McGill University Health Centre, Montreal, Qc, Canada
- Department of Human Genetics, Faculty of Medicine, McGill University, Montreal, Qc, Canada
| | - Francesco Brancati
- Department of Life, Human Genetics, Health and Environmental Sciences, University of L’Aquila, L’Aquila, Italy
- IRCCS San Raffaele Roma, Rome, Italy
| | - Fabio Benfenati
- Center for Synaptic Neuroscience and Technology, Istituto Italiano di Tecnologia, Geneva, Italy
- IRCCS Ospedale Policlinico San Martino, Geneva, Italy
| | - Nicolas Chatron
- Service de Genetique, Hospices Civils de Lyon, Bron, France
- Institute NeuroMyoGène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, CNRS UMR 5261 -INSERM U1315, Université de Lyon - Université Claude Bernard Lyon 1, Lyon, France
| | - David Lewis-Smith
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom
- Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
| | - Rhys H. Thomas
- Translational and Clinical Research Institute, Newcastle University, Newcastle Upon Tyne, United Kingdom
- Department of Clinical Neurosciences, Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle Upon Tyne, United Kingdom
| | - Federico Zara
- IRCCS G. Gaslini, Genova, Italy
- Department of Neurology, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
| | - Pasquale Striano
- IRCCS G. Gaslini, Genova, Italy
- Department of Neurology, Rehabilitation, Ophtalmology, Genetics, Maternal and Child Health, University of Genova, Genova, Italy
| | - Gaetan Lesca
- Service de Genetique, Hospices Civils de Lyon, Bron, France
- Institute NeuroMyoGène, Laboratoire Physiopathologie et Génétique du Neurone et du Muscle, CNRS UMR 5261 -INSERM U1315, Université de Lyon - Université Claude Bernard Lyon 1, Lyon, France
| | - Christel Depienne
- Institute of Human Genetics, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| |
Collapse
|
|
11
|
Exome sequencing allows detection of relevant pharmacogenetic variants in epileptic patients. THE PHARMACOGENOMICS JOURNAL 2022; 22:258-263. [PMID: 35590072 DOI: 10.1038/s41397-022-00280-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 04/28/2022] [Accepted: 05/09/2022] [Indexed: 01/08/2023]
Abstract
Beyond the identification of causal genetic variants in the diagnosis of Mendelian disorders, exome sequencing can detect numerous variants with potential relevance for clinical care. Clinical interventions can thus be conducted to improve future health outcomes for patients and their at-risk relatives, such as predicting late-onset genetic disorders accessible to prevention, treatment or identifying differential drug efficacy and safety. To evaluate the interest of such pharmacogenetic information, we designed an "in house" pipeline to determine the status of 122 PharmGKB (Pharmacogenomics Knowledgebase) variant-drug combinations in 31 genes. This pipeline was applied to a cohort of 90 epileptic patients who had previously an exome sequencing (ES) analysis, to determine the frequency of pharmacogenetic variants. We performed a retrospective analysis of drug plasma concentrations and treatment efficacy in patients bearing at least one relevant PharmGKB variant. For PharmGKB level 1A variants, CYP2C9 status for phenytoin prescription was the only relevant information. Nineteen patients were treated with phenytoin, among phenytoin-treated patients, none were poor metabolizers and four were intermediate metabolizers. While being treated with a standard protocol (10-23 mg/kg/30 min loading dose followed by 5 mg/kg/8 h maintenance dose), all identified intermediate metabolizers had toxic plasma concentrations (20 mg/L). In epileptic patients, pangenomic sequencing can provide information about common pharmacogenetic variants likely to be useful to guide therapeutic drug monitoring, and in the case of phenytoin, to prevent clinical toxicity caused by high plasma levels.
Collapse
|
|
12
|
Kasak L, Lillepea K, Nagirnaja L, Aston KI, Schlegel PN, Gonçalves J, Carvalho F, Moreno-Mendoza D, Almstrup K, Eisenberg ML, Jarvi KA, O’Bryan MK, Lopes AM, Conrad DF. Actionable secondary findings following exome sequencing of 836 non-obstructive azoospermia cases and their value in patient management. Hum Reprod 2022; 37:1652-1663. [PMID: 35535697 PMCID: PMC9631463 DOI: 10.1093/humrep/deac100] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2022] [Revised: 04/10/2022] [Indexed: 11/14/2022] Open
Abstract
STUDY QUESTION What is the load, distribution and added clinical value of secondary findings (SFs) identified in exome sequencing (ES) of patients with non-obstructive azoospermia (NOA)? SUMMARY ANSWER One in 28 NOA cases carried an identifiable, medically actionable SF. WHAT IS KNOWN ALREADY In addition to molecular diagnostics, ES allows assessment of clinically actionable disease-related gene variants that are not connected to the patient's primary diagnosis, but the knowledge of which may allow the prevention, delay or amelioration of late-onset monogenic conditions. Data on SFs in specific clinical patient groups, including reproductive failure, are currently limited. STUDY DESIGN, SIZE, DURATION The study group was a retrospective cohort of patients with NOA recruited in 10 clinics across six countries and formed in the framework of the international GEMINI (The GEnetics of Male INfertility Initiative) study. PARTICIPANTS/MATERIALS, SETTING, METHODS ES data of 836 patients with NOA were exploited to analyze SFs in 85 genes recommended by the American College of Medical Genetics and Genomics (ACMG), Geisinger's MyCode, and Clinical Genome Resource. The identified 6374 exonic variants were annotated with ANNOVAR and filtered for allele frequency, retaining 1381 rare or novel missense and loss-of-function variants. After automatic assessment of pathogenicity with ClinVar and InterVar, 87 variants were manually curated. The final list of confident disease-causing SFs was communicated to the corresponding GEMINI centers. When patient consent had been given, available family health history and non-andrological medical data were retrospectively assessed. MAIN RESULTS AND THE ROLE OF CHANCE We found a 3.6% total frequency of SFs, 3.3% from the 59 ACMG SF v2.0 genes. One in 70 patients carried SFs in genes linked to familial cancer syndromes, whereas 1 in 60 cases was predisposed to congenital heart disease or other cardiovascular conditions. Retrospective assessment confirmed clinico-molecular diagnoses in several cases. Notably, 37% (11/30) of patients with SFs carried variants in genes linked to male infertility in mice, suggesting that some SFs may have a co-contributing role in spermatogenic impairment. Further studies are needed to determine whether these observations represent chance findings or the profile of SFs in NOA patients is indeed different from the general population. LIMITATIONS, REASONS FOR CAUTION One limitation of our cohort was the low proportion of non-Caucasian ethnicities (9%). Additionally, as comprehensive clinical data were not available retrospectively for all men with SFs, we were not able to confirm a clinico-molecular diagnosis and assess the penetrance of the specific variants. WIDER IMPLICATIONS OF THE FINDINGS For the first time, this study analyzed medically actionable SFs in men with spermatogenic failure. With the evolving process to incorporate ES into routine andrology practice for molecular diagnostic purposes, additional assessment of SFs can inform about future significant health concerns for infertility patients. Timely detection of SFs and respective genetic counseling will broaden options for disease prevention and early treatment, as well as inform choices and opportunities regarding family planning. A notable fraction of SFs was detected in genes implicated in maintaining genome integrity, essential in both mitosis and meiosis. Thus, potential genetic pleiotropy may exist between certain adult-onset monogenic diseases and NOA. STUDY FUNDING/COMPETING INTEREST(S) This work was supported by the Estonian Research Council grants IUT34-12 and PRG1021 (M.L. and M.P.); National Institutes of Health of the United States of America grant R01HD078641 (D.F.C., K.I.A. and P.N.S.); National Institutes of Health of the United States of America grant P50HD096723 (D.F.C. and P.N.S.); National Health and Medical Research Council of Australia grant APP1120356 (M.K.O'B., D.F.C. and K.I.A.); Fundação para a Ciência e a Tecnologia (FCT)/Ministério da Ciência, Tecnologia e Inovação grant POCI-01-0145-FEDER-007274 (A.M.L., F.C. and J.G.) and FCT: IF/01262/2014 (A.M.L.). J.G. was partially funded by FCT/Ministério da Ciência, Tecnologia e Ensino Superior (MCTES), through the Centre for Toxicogenomics and Human Health-ToxOmics (grants UID/BIM/00009/2016 and UIDB/00009/2020). M.L.E. is a consultant for, and holds stock in, Roman, Sandstone, Dadi, Hannah, Underdog and has received funding from NIH/NICHD. Co-authors L.K., K.L., L.N., K.I.A., P.N.S., J.G., F.C., D.M.-M., K.A., K.A.J., M.K.O'B., A.M.L., D.F.C., M.P. and M.L. declare no conflict of interest. TRIAL REGISTRATION NUMBER N/A.
Collapse
Affiliation(s)
- Laura Kasak
- Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Kristiina Lillepea
- Department of Biomedicine, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia
| | - Liina Nagirnaja
- Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
| | - Kenneth I Aston
- Andrology and IVF Laboratory, Department of Surgery (Urology), University of Utah School of Medicine, Salt Lake City, UT, USA
| | - Peter N Schlegel
- Department of Urology, Weill Cornell Medicine, New York, NY, USA
| | - João Gonçalves
- Departamento de Genética Humana, Instituto Nacional de Saúde Dr. Ricardo Jorge, Lisboa, Portugal,Centre for Toxicogenomics and Human Health—ToxOmics, Nova Medical School, Lisbon, Portugal
| | - Filipa Carvalho
- Serviço de Genética, Departamento de Patologia, Faculdade de Medicina da Universidade do Porto, Porto, Portugal,i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal
| | - Daniel Moreno-Mendoza
- Andrology Department, Fundació Puigvert, Universitat Autònoma de Barcelona, Instituto de Investigaciones Biomédicas Sant Pau (IIB-Sant Pau), Barcelona, Spain,Department of Urology, Hospital Francisco Grande Covián, Arriondas, Asturias, Spain
| | - Kristian Almstrup
- Department of Growth and Reproduction, Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark,International Center for Research and Research Training in Endocrine Disruption of Male Reproduction and Child Health (EDMaRC), Copenhagen University Hospital—Rigshospitalet, Copenhagen, Denmark
| | - Michael L Eisenberg
- Department of Urology, Stanford University School of Medicine, Stanford, CA, USA
| | - Keith A Jarvi
- Division of Urology, Department of Surgery, Mount Sinai Hospital, University of Toronto, Toronto, ON, Canada
| | - Moira K O’Bryan
- School of BioSciences and Bio21 Institute, Faculty of Science, The University of Melbourne, Parkville, Australia
| | - Alexandra M Lopes
- i3S—Instituto de Investigação e Inovação em Saúde, University of Porto, Porto, Portugal,IPATIMUP—Instituto de Patologia e Imunologia Molecular da Universidade do Porto, Porto, Portugal
| | - Donald F Conrad
- Division of Genetics, Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, USA
| |
Collapse
|
|
13
|
Cheung F, Birch P, Friedman JM, Elliott AM, Adam S. The long‐term impact of receiving incidental findings on parents undergoing genome‐wide sequencing. J Genet Couns 2022; 31:887-900. [DOI: 10.1002/jgc4.1558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 11/08/2022]
Affiliation(s)
- Faith Cheung
- Department of Medical Genetics Faculty of Medicine University of British Columbia Vancouver British Columbia Canada
| | - Patricia Birch
- Department of Medical Genetics Faculty of Medicine University of British Columbia Vancouver British Columbia Canada
- BC Children’s Hospital Research Institute Vancouver British Columbia Canada
| | - J. M. Friedman
- Department of Medical Genetics Faculty of Medicine University of British Columbia Vancouver British Columbia Canada
- BC Children’s Hospital Research Institute Vancouver British Columbia Canada
| | - Alison M Elliott
- Department of Medical Genetics Faculty of Medicine University of British Columbia Vancouver British Columbia Canada
- BC Children’s Hospital Research Institute Vancouver British Columbia Canada
- BC Women’s Health Research Institute Vancouver British Columbia Canada
| | - Shelin Adam
- Department of Medical Genetics Faculty of Medicine University of British Columbia Vancouver British Columbia Canada
- BC Children’s Hospital Research Institute Vancouver British Columbia Canada
| | | | | |
Collapse
|
|
14
|
Haga SB. Revisiting Secondary Information Related to Pharmacogenetic Testing. Front Genet 2021; 12:741395. [PMID: 34659361 PMCID: PMC8517135 DOI: 10.3389/fgene.2021.741395] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 09/13/2021] [Indexed: 12/22/2022] Open
Abstract
Incidental or secondary findings have been a major part of the discussion of genomic medicine research and clinical applications. For pharmacogenetic (PGx) testing, secondary findings arise due to the pleiotropic effects of pharmacogenes, often related to their endogenous functions. Unlike the guidelines that have been developed for whole exome or genome sequencing applications for management of secondary findings (though slightly different from PGx testing in that these refer to detection of variants in multiple genes, some with clinical significance and actionability), no corresponding guidelines have been developed for PGx clinical laboratories. Nonetheless, patient and provider education will remain key components of any PGx testing program to minimize adverse responses related to secondary findings.
Collapse
|
|
15
|
Ng YS, Bindoff LA, Gorman GS, Klopstock T, Kornblum C, Mancuso M, McFarland R, Sue CM, Suomalainen A, Taylor RW, Thorburn DR, Turnbull DM. Mitochondrial disease in adults: recent advances and future promise. Lancet Neurol 2021; 20:573-584. [PMID: 34146515 DOI: 10.1016/s1474-4422(21)00098-3] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/17/2021] [Accepted: 03/17/2021] [Indexed: 02/07/2023]
Abstract
Mitochondrial diseases are some of the most common inherited neurometabolic disorders, and major progress has been made in our understanding, diagnosis, and treatment of these conditions in the past 5 years. Development of national mitochondrial disease cohorts and international collaborations has changed our knowledge of the spectrum of clinical phenotypes and natural history of mitochondrial diseases. Advances in high-throughput sequencing technologies have altered the diagnostic algorithm for mitochondrial diseases by increasingly using a genetics-first approach, with more than 350 disease-causing genes identified to date. While the current management strategy for mitochondrial disease focuses on surveillance for multisystem involvement and effective symptomatic treatment, new endeavours are underway to find better treatments, including repurposing current drugs, use of novel small molecules, and gene therapies. Developments made in reproductive technology offer women the opportunity to prevent transmission of DNA-related mitochondrial disease to their children.
Collapse
Affiliation(s)
- Yi Shiau Ng
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Laurence A Bindoff
- Department of Clinical Medicine, University of Bergen, Bergen, Norway; Neuro-SysMed, Department of Neurology, Haukeland University Hospital, Bergen, Norway
| | - Gráinne S Gorman
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK; Directorate of Neurosciences, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Thomas Klopstock
- Department of Neurology, Friedrich-Baur-Institute, LMU Hospital, Ludwig Maximilians University, Munich, Germany; German Center for Neurodegenerative Diseases, Munich, Germany; Munich Cluster for Systems Neurology, Munich, Germany
| | - Cornelia Kornblum
- Department of Neurology, Neuromuscular Disease Section, University Hospital Bonn, Bonn, Germany; Centre for Rare Diseases, University Hospital Bonn, Bonn, Germany
| | - Michelangelo Mancuso
- Department of Clinical and Experimental Medicine, Neurological Institute, University of Pisa, Italy
| | - Robert McFarland
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - Carolyn M Sue
- Department of Neurogenetics, Kolling Institute, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia; Department of Neurology, Royal North Shore Hospital, Northern Sydney Local Health District, St Leonards, NSW, Australia
| | - Anu Suomalainen
- Research Program in Stem Cells and Metabolism, Faculty of Medicine, University of Helsinki, Helsinki, Finland; Neuroscience Centre, HiLife, University of Helsinki, Helsinki, Finland; Helsinki University Hospital, HUSlab, Helsinki, Finland
| | - Robert W Taylor
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - David R Thorburn
- Murdoch Children's Research Institute, Royal Children's Hospital, Melbourne, VIC, Australia; Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, VIC, Australia; Department of Paediatrics, University of Melbourne, Melbourne, VIC, Australia
| | - Doug M Turnbull
- Wellcome Centre for Mitochondrial Research, Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; NHS Highly Specialised Service for Rare Mitochondrial Disorders, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK.
| |
Collapse
|
|
16
|
Wang Z, Xu H, Xiang T, Liu D, Xu F, Zhao L, Feng Y, Xu L, Liu J, Fang Y, Liu H, Li R, Hu X, Guan J, Liu L, Feng G, Shen Q, Xu H, Frishman D, Tang W, Guo J, Rao J, Shang W. An accessible insight into genetic findings for transplantation recipients with suspected genetic kidney disease. NPJ Genom Med 2021; 6:57. [PMID: 34215756 PMCID: PMC8253729 DOI: 10.1038/s41525-021-00219-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Accepted: 06/10/2021] [Indexed: 02/07/2023] Open
Abstract
Determining the etiology of end-stage renal disease (ESRD) constitutes a great challenge in the context of renal transplantation. Evidence is lacking on the genetic findings for adult renal transplant recipients through exome sequencing (ES). Adult patients on kidney transplant waitlist were recruited from 2017 to 2019. Trio-ES was conducted for the families who had multiple affected individuals with nephropathy or clinical suspicion of a genetic kidney disease owing to early onset or extrarenal features. Pathogenic variants were confirmed in 62 from 115 families post sequencing for 421 individuals including 195 health family members as potential living donors. Seventeen distinct genetic disorders were identified confirming the priori diagnosis in 33 (28.7%) families, modified or reclassified the clinical diagnosis in 27 (23.5%) families, and established a diagnosis in two families with ESRD of unknown etiology. In 14.8% of the families, we detected promising variants of uncertain significance in candidate genes associated with renal development or renal disease. Furthermore, we reported the secondary findings of oncogenes in 4.4% of the patients and known single-nucleotide polymorphisms associated with pharmacokinetics in our cohort to predict the drug levels of tacrolimus and mycophenolate. The diagnostic utility of the genetic findings has provided new clinical insight in most families that help with preplanned renal transplantation.
Collapse
Affiliation(s)
- Zhigang Wang
- Department of Kidney Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Hongen Xu
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Tianchao Xiang
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Danhua Liu
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.,The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Fei Xu
- Department of Kidney Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Lixiang Zhao
- Department of Kidney Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Yonghua Feng
- Department of Kidney Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Linan Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Jialu Liu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Ye Fang
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Huanfei Liu
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Ruijun Li
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Xinxin Hu
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jingyuan Guan
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Longshan Liu
- Organ Transplant Center, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Guiwen Feng
- Department of Kidney Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Qian Shen
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Hong Xu
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China.,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China
| | - Dmitrij Frishman
- Department of Bioinformatics, Technische Universität München, Freising, Germany
| | - Wenxue Tang
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China.,The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China
| | - Jiancheng Guo
- Precision Medicine Center of Zhengzhou University, Academy of Medical Sciences, Zhengzhou University, Zhengzhou, Henan, China. .,The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. .,Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, Henan, China.
| | - Jia Rao
- Department of Nephrology, Children's Hospital of Fudan University, Shanghai, China. .,Shanghai Key Lab of Birth Defect, Children's Hospital of Fudan University, Shanghai, China. .,State Key Laboratory of Medical Neurobiology, Institutes of Brain Science and School of Basic Medical Science, Fudan University, Shanghai, China.
| | - Wenjun Shang
- Department of Kidney Transplantation, First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| |
Collapse
|
|
17
|
Nambot S, Sawka C, Bertolone G, Cosset E, Goussot V, Derangère V, Boidot R, Baurand A, Robert M, Coutant C, Loustalot C, Thauvin-Robinet C, Ghiringhelli F, Lançon A, Populaire C, Damette A, Collonge-Rame MA, Meunier-Beillard N, Lejeune C, Albuisson J, Faivre L. Incidental findings in a series of 2500 gene panel tests for a genetic predisposition to cancer: Results and impact on patients. Eur J Med Genet 2021; 64:104196. [PMID: 33753322 DOI: 10.1016/j.ejmg.2021.104196] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Revised: 02/02/2021] [Accepted: 03/14/2021] [Indexed: 10/21/2022]
Abstract
With next generation sequencing, physicians are faced with more complex and uncertain data, particularly incidental findings (IF). Guidelines for the return of IF have been published by learned societies. However, little is known about how patients are affected by these results in a context of oncogenetic testing. Over 4 years, 2500 patients with an indication for genetic testing underwent a gene cancer panel. If an IF was detected, patients were contacted by a physician/genetic counsellor and invited to take part in a semi-structured interview to assess their understanding of the result, the change in medical care, the psychological impact, and the transmission of results to the family. Fourteen patients (0.56%) were delivered an IF in a cancer predisposition gene (RAD51C, PMS2, SDHC, RET, BRCA2, CHEK2, CDKN2A, CDH1, SUFU). Two patients did not collect the results and another two died before the return of results. Within the 10 patients recontacted, most of them reported surprise at the delivery of IF, but not anxiety. The majority felt they had chosen to obtain the result and enough information to understand it. They all initiated the recommended follow-up and did not regret the procedure. Information regarding the IF was transmitted to their offspring but siblings or second-degree relatives were not consistently informed. No major adverse psychological events were found in our experience. IF will be inherent to the development of sequencing, even for restricted gene panels, so it is important to increase our knowledge on the impact of such results in different contexts.
Collapse
Affiliation(s)
- S Nambot
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France; CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France.
| | - C Sawka
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France; CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France
| | - G Bertolone
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France; CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France
| | - E Cosset
- CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France
| | - V Goussot
- Platform of Transfer in Cancer Biology, Department of Biology and Pathology of Tumours, Centre Georges-François Leclerc, Unicancer, F-21000, Dijon, France
| | - V Derangère
- Platform of Transfer in Cancer Biology, Department of Biology and Pathology of Tumours, Centre Georges-François Leclerc, Unicancer, F-21000, Dijon, France
| | - R Boidot
- Platform of Transfer in Cancer Biology, Department of Biology and Pathology of Tumours, Centre Georges-François Leclerc, Unicancer, F-21000, Dijon, France; CNRS, 6302 Unit, Dijon, France
| | - A Baurand
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France; CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France
| | - M Robert
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France
| | - C Coutant
- Département de Chirurgie, Centre Georges François Leclerc, F-21000, Dijon, France
| | - C Loustalot
- Département de Chirurgie, Centre Georges François Leclerc, F-21000, Dijon, France
| | - C Thauvin-Robinet
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France
| | - F Ghiringhelli
- Platform of Transfer in Cancer Biology, Department of Biology and Pathology of Tumours, Centre Georges-François Leclerc, Unicancer, F-21000, Dijon, France; Département D'oncologie Médicale, Centre Georges François Leclerc, Dijon, France; Centre de Recherche INSERM LNC-UMR123, Université de Bourgogne Franche-Comté, F-21000, Dijon, France
| | - A Lançon
- CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France
| | - C Populaire
- Service Génétique et Biologie Du Développement-Histologie, CHU Hôpital Saint-Jacques, Besançon, France
| | - A Damette
- Service Génétique et Biologie Du Développement-Histologie, CHU Hôpital Saint-Jacques, Besançon, France
| | - M A Collonge-Rame
- Service Génétique et Biologie Du Développement-Histologie, CHU Hôpital Saint-Jacques, Besançon, France
| | - N Meunier-Beillard
- INSERM, CIC1432, Module épidémiologie Clinique, Dijon, France; Centre Hospitalier Universitaire Dijon-Bourgogne, Centre D'investigation Clinique, Module épidémiologie Clinique/essais Cliniques, Dijon, France
| | - C Lejeune
- Centre de Recherche INSERM LNC-UMR123, Université de Bourgogne Franche-Comté, F-21000, Dijon, France; INSERM, CIC1432, Module épidémiologie Clinique, Dijon, France; Centre Hospitalier Universitaire Dijon-Bourgogne, Centre D'investigation Clinique, Module épidémiologie Clinique/essais Cliniques, Dijon, France
| | - J Albuisson
- Platform of Transfer in Cancer Biology, Department of Biology and Pathology of Tumours, Centre Georges-François Leclerc, Unicancer, F-21000, Dijon, France; Centre de Recherche INSERM LNC-UMR123, Université de Bourgogne Franche-Comté, F-21000, Dijon, France
| | - L Faivre
- Centre de Génétique, FHU TRANSLAD, Institut GIMI, CHU Dijon, F-21000, Dijon, France; CGFL, Unité D'oncogénétique et Institut GIMI, F-21000, Dijon, France.
| |
Collapse
|
|
18
|
Vears DF, Borry P, Savulescu J, Koplin JJ. Old Challenges or New Issues? Genetic Health Professionals' Experiences Obtaining Informed Consent in Diagnostic Genomic Sequencing. AJOB Empir Bioeth 2020; 12:12-23. [PMID: 33017265 PMCID: PMC8120994 DOI: 10.1080/23294515.2020.1823906] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Background While integrating genomic sequencing into clinical care carries clear medical benefits, it also raises difficult ethical questions. Compared to traditional sequencing technologies, genomic sequencing and analysis is more likely to identify unsolicited findings (UF) and variants that cannot be classified as benign or disease-causing (variants of uncertain significance; VUS). UF and VUS pose new challenges for genetic health professionals (GHPs) who are obtaining informed consent for genomic sequencing from patients. Methods We conducted semi-structured interviews with 31 GHPs across Europe, Australia and Canada to identify some of these challenges. Results Our results show that GHPs find it difficult to prepare patients to receive results because a vast amount of information is required to fully inform patients about VUS and UF. GHPs also struggle to engage patients – many of whom may be focused on ending their ‘diagnostic odyssey’ – in the informed consent process in a meaningful way. Thus, some questioned how ‘informed’ patients actually are when they agree to undergo clinical genomic sequencing. Conclusions These findings suggest a tension remains between sufficient information provision at the risk of overwhelming the patient and imparting less information at the risk of uninformed decision-making. We suggest that a shift away from ‘fully informed consent’ toward an approach aimed at realizing, as far as possible, the underlying goals that informed consent is meant to promote.
Collapse
Affiliation(s)
- Danya F Vears
- Melbourne Law School, University of Melbourne, Parkville, Australia.,Biomedical Ethics Research Group, Murdoch Children's Research Institute, Parkville, Australia.,Department of Public Health and Primary Care, Center for Biomedical Ethics and Law, Leuven, Belgium.,Leuven Institute for Human Genetics and Society, Leuven, Belgium
| | - Pascal Borry
- Department of Public Health and Primary Care, Center for Biomedical Ethics and Law, Leuven, Belgium.,Leuven Institute for Human Genetics and Society, Leuven, Belgium
| | - Julian Savulescu
- Melbourne Law School, University of Melbourne, Parkville, Australia.,Biomedical Ethics Research Group, Murdoch Children's Research Institute, Parkville, Australia.,Oxford Uehiro Centre for Practical Ethics, University of Oxford, Oxford, UK.,Wellcome Centre for Ethics and Humanities, University of Oxford, Oxford, UK
| | - Julian J Koplin
- Melbourne Law School, University of Melbourne, Parkville, Australia.,Biomedical Ethics Research Group, Murdoch Children's Research Institute, Parkville, Australia
| |
Collapse
|
|
19
|
Haga SB, Orlando LA. The enduring importance of family health history in the era of genomic medicine and risk assessment. Per Med 2020; 17:229-239. [PMID: 32320338 DOI: 10.2217/pme-2019-0091] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Improving disease risk prediction and tailoring preventive interventions to patient risk factors is one of the primary goals of precision medicine. Family health history is the traditional approach to quickly gather genetic and environmental data relevant to the patient. While the utility of family health history is well-documented, its utilization is variable, in part due to lack of patient and provider knowledge and incomplete or inaccurate data. With the advances and reduced costs of sequencing technologies, comprehensive sequencing tests can be performed as a risk assessment tool. We provide an overview of each of these risk assessment approaches, the benefits and limitations and implementation challenges.
Collapse
Affiliation(s)
- Susanne B Haga
- Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, 101 Science Drive, Box 3382, Durham, NC 27708, USA
| | - Lori A Orlando
- Center for Applied Genomics & Precision Medicine, Duke University School of Medicine, 101 Science Drive, Box 3382, Durham, NC 27708, USA
| |
Collapse
|
|
20
|
Diebold I, Schön U, Scharf F, Benet-Pagès A, Laner A, Holinski-Feder E, Abicht A. Critical assessment of secondary findings in genes linked to primary arrhythmia syndromes. Hum Mutat 2020; 41:1025-1032. [PMID: 32048431 PMCID: PMC7187207 DOI: 10.1002/humu.23996] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 01/16/2020] [Accepted: 02/09/2020] [Indexed: 12/15/2022]
Abstract
As comprehensive sequencing technologies gain widespread use, questions about so-called secondary findings (SF) require urgent consideration. The American College of Medical Genetics and Genomics has recommended to report SF in 59 genes (ACMG SF v2.0) including four actionable genes associated with inherited primary arrhythmia syndromes (IPAS) such as catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, and Brugada syndrome. Databases provide conflicting results for the purpose of identifying pathogenic variants in SF associated with IPAS at a level of sufficient evidence for clinical return. As IPAS account for a significant proportion of sudden cardiac deaths (SCD) in young and apparently healthy individuals, variant interpretation has a great impact on diagnosis and prevention of disease. Of 6381 individuals, 0.4% carry pathogenic variants in one of the four actionable genes related to IPAS: RYR2, KCNQ1, KCNH2, and SCN5A. Comparison of the databases ClinVar, Leiden Open-source Variant Database, and Human Gene Mutation Database showed impactful differences (0.2% to 1.3%) in variant interpretation improvable by expert-curation depending on database and classification system used. These data further highlight the need for international consensus regarding the variant interpretation, and subsequently management of SF in particular with regard to treatable arrhythmic disorders with increased risk of SCD.
Collapse
Affiliation(s)
- Isabel Diebold
- Department of Genomics, Medical Genetics Center Munich, Munich, Germany.,Department of Pediatrics, Technical University of Munich School of Medicine, Munich, Germany
| | - Ulrike Schön
- Department of Genomics, Medical Genetics Center Munich, Munich, Germany
| | - Florentine Scharf
- Department of Genomics, Medical Genetics Center Munich, Munich, Germany
| | - Anna Benet-Pagès
- Department of Genomics, Medical Genetics Center Munich, Munich, Germany
| | - Andreas Laner
- Department of Genomics, Medical Genetics Center Munich, Munich, Germany
| | | | - Angela Abicht
- Department of Genomics, Medical Genetics Center Munich, Munich, Germany.,Department of Neurology, Friedrich-Baur-Institute, Klinikum der Ludwig-Maximilians-University, Munich, Germany
| |
Collapse
|