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Van Steijvoort E, Borry P. Ethical and Practical Considerations in Implementing Population-Based Reproductive Genetic Carrier Screening. Genes (Basel) 2025; 16:423. [PMID: 40282381 PMCID: PMC12026641 DOI: 10.3390/genes16040423] [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: 02/18/2025] [Revised: 03/28/2025] [Accepted: 03/29/2025] [Indexed: 04/29/2025] Open
Abstract
Reproductive genetic carrier screening (RGCS) has emerged as a promising tool for identifying couples with an increased likelihood of conceiving a child with an autosomal recessive or X-linked genetic condition. By enabling early detection, RGCS has the potential to support informed reproductive decision-making. Historically, carrier screening initiatives aimed to decrease the prevalence of specific genetic disorders by targeting particular high-risk populations. More recently, there has been a shift towards offering RGCS for a wider range of conditions, with the goal of enhancing reproductive autonomy by facilitating informed decision-making and addressing inequities in access to healthcare interventions. However, this shift towards a more inclusive, population-based approach has raised questions about the tension between individual autonomy and public health goals, as well as concerns regarding the potential negative effects of large-scale genetic screening initiatives. Furthermore, there is growing interest in utilizing RGCS data for broader purposes, such as population-based genetic screening programs for hereditary cancers or identifying causes of unexplained infertility, which may present additional ethical considerations. This review explores the complexities surrounding the implementation of RGCS, with an emphasis on its objectives, the significance of informed decision-making, and the wider societal challenges it may present. By analyzing these interconnected factors, we aim to provide a thorough understanding of the potential implications of RGCS on both individual autonomy and societal dynamics.
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Affiliation(s)
- Eva Van Steijvoort
- Centre for Biomedical Ethics and Law, Department of Public Health and Primary Care, KU Leuven, Kapucijnenvoer 7 bus 7001, 3000 Leuven, Belgium;
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Kristoffersson U, Johansson-Soller M. Pregnancy Planning and Genetic Testing: Exploring Advantages, and Challenges. Genes (Basel) 2024; 15:1205. [PMID: 39336796 PMCID: PMC11431595 DOI: 10.3390/genes15091205] [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: 07/16/2024] [Revised: 08/30/2024] [Accepted: 09/04/2024] [Indexed: 09/30/2024] Open
Abstract
Pregnancy planning and genetic testing (PPGT) has emerged as a tool in reproductive healthcare, offering parents-to-be insight in their risks of having a child with a genetic disorder. This paper reviews the advantages, drawbacks and challenges associated with PPGT, providing some practical guidance for health care professionals. Advantages include identification of genetic risks, a possibility to informed reproductive decision-making, and the potential to reduce the parents-to-be risk for an affected child. Challenges and drawbacks include provision of service, ethical considerations, genetic counselling complexities, and the need to increase public and professional awareness by comprehensive education and accessibility. Practical guidance involves considerations for selecting appropriate candidates, counselling strategies, and how to integrate PPGT into existing healthcare frameworks. By addressing these factors, PPGT can offer an increased reproductive informed choice for the individual and the couple reducing the burden of disease in the family.
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Affiliation(s)
- Ulf Kristoffersson
- Division of Clinical Genetics, Department of Laboratory Medicine, Lund University, 22100 Lund, Sweden
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Panzaru MC, Florea A, Caba L, Gorduza EV. Classification of osteogenesis imperfecta: Importance for prophylaxis and genetic counseling. World J Clin Cases 2023; 11:2604-2620. [PMID: 37214584 PMCID: PMC10198117 DOI: 10.12998/wjcc.v11.i12.2604] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Revised: 03/18/2023] [Accepted: 03/27/2023] [Indexed: 04/25/2023] Open
Abstract
Osteogenesis imperfecta (OI) is a genetically heterogeneous monogenic disease characterized by decreased bone mass, bone fragility, and recurrent fractures. The phenotypic spectrum varies considerably ranging from prenatal fractures with lethal outcomes to mild forms with few fractures and normal stature. The basic mechanism is a collagen-related defect, not only in synthesis but also in folding, processing, bone mineralization, or osteoblast function. In recent years, great progress has been made in identifying new genes and molecular mechanisms underlying OI. In this context, the classification of OI has been revised several times and different types are used. The Sillence classification, based on clinical and radiological characteristics, is currently used as a grading of clinical severity. Based on the metabolic pathway, the functional classification allows identifying regulatory elements and targeting specific therapeutic approaches. Genetic classification has the advantage of identifying the inheritance pattern, an essential element for genetic counseling and prophylaxis. Although genotype-phenotype correlations may sometimes be challenging, genetic diagnosis allows a personalized management strategy, accurate family planning, and pregnancy management decisions including options for mode of delivery, or early antenatal OI treatment. Future research on molecular pathways and pathogenic variants involved could lead to the development of genotype-based therapeutic approaches. This narrative review summarizes our current understanding of genes, molecular mechanisms involved in OI, classifications, and their utility in prophylaxis.
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Affiliation(s)
- Monica-Cristina Panzaru
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Andreea Florea
- Department of Medical Genetics - Medical Genetics resident, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Lavinia Caba
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Eusebiu Vlad Gorduza
- Department of Medical Genetics, Faculty of Medicine, “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Xiao Q, Lauschke VM. The prevalence, genetic complexity and population-specific founder effects of human autosomal recessive disorders. NPJ Genom Med 2021; 6:41. [PMID: 34078906 PMCID: PMC8172936 DOI: 10.1038/s41525-021-00203-x] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Accepted: 05/05/2021] [Indexed: 11/13/2022] Open
Abstract
Autosomal recessive (AR) disorders pose a significant burden for public health. However, despite their clinical importance, epidemiology and molecular genetics of many AR diseases remain poorly characterized. Here, we analyzed the genetic variability of 508 genes associated with AR disorders based on sequencing data from 141,456 individuals across seven ethnogeographic groups by integrating variants with documented pathogenicity from ClinVar, with stringent functionality predictions for variants with unknown pathogenicity. We first validated our model using 85 diseases for which population-specific prevalence data were available and found that our estimates strongly correlated with the respective clinically observed disease frequencies (r = 0.68; p < 0.0001). We found striking differences in population-specific disease prevalence with 101 AR diseases (27%) being limited to specific populations, while an additional 305 diseases (68%) differed more than tenfold across major ethnogeographic groups. Furthermore, by analyzing genetic AR disease complexity, we confirm founder effects for cystic fibrosis and Stargardt disease, and provide strong evidences for >25 additional population-specific founder mutations. The presented analyses reveal the molecular genetics of AR diseases with unprecedented resolution and provide insights into epidemiology, complexity, and population-specific founder effects. These data can serve as a powerful resource for clinical geneticists to inform population-adjusted genetic screening programs, particularly in otherwise understudied ethnogeographic groups.
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Affiliation(s)
- Qingyang Xiao
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden
| | - Volker M Lauschke
- Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
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Jain A, Sharma D, Bajaj A, Gupta V, Scaria V. Founder variants and population genomes-Toward precision medicine. ADVANCES IN GENETICS 2021; 107:121-152. [PMID: 33641745 DOI: 10.1016/bs.adgen.2020.11.004] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
Human migration and community specific cultural practices have contributed to founder events and enrichment of the variants associated with genetic diseases. While many founder events in isolated populations have remained uncharacterized, the application of genomics in clinical settings as well as for population scale studies in the recent years have provided an unprecedented push towards identification of founder variants associated with human health and disease. The discovery and characterization of founder variants could have far reaching implications not only in understanding the history or genealogy of the disease, but also in implementing evidence based policies and genetic testing frameworks. This further enables precise diagnosis and prevention in an attempt towards precision medicine. This review provides an overview of founder variants along with methods and resources cataloging them. We have also discussed the public health implications and examples of prevalent disease associated founder variants in specific populations.
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Affiliation(s)
- Abhinav Jain
- CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Disha Sharma
- CSIR-Institute of Genomics and Integrative Biology, New Delhi, India
| | - Anjali Bajaj
- CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Vishu Gupta
- CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India
| | - Vinod Scaria
- CSIR-Institute of Genomics and Integrative Biology, New Delhi, India; Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, Uttar Pradesh, India.
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Nijmeijer SCM, Conijn T, Lakeman P, Henneman L, Wijburg FA, Haverman L. Attitudes of the general population towards preconception expanded carrier screening for autosomal recessive disorders including inborn errors of metabolism. Mol Genet Metab 2019; 126:14-22. [PMID: 30563741 DOI: 10.1016/j.ymgme.2018.12.004] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 12/05/2018] [Accepted: 12/07/2018] [Indexed: 11/16/2022]
Abstract
BACKGROUND A substantial number of severely debilitating and often ultimately fatal inborn errors of metabolism (IEMs) still lack an effective disease-modifying treatment. Informing couples before a pregnancy about an increased risk of having a child with an inherited disorder is now feasible by preconception expanded carrier screening (ECS). While knowledge about carrier status enhances reproductive autonomy, it may also result in ethical dilemmas. The purpose of this study was to assess the attitudes of the general Dutch population towards preconception ECS and to investigate which factors influence these attitudes. METHODS Data collection was carried out in collaboration with a market research agency. In total, 1188 Dutch individuals of reproductive age (18-45 years) were invited by email to complete an online ECS questionnaire in 2016. Prior to the start of the questionnaire, a written explanation of the concepts of autosomal recessive (AR) inheritance, carrier status and ECS was presented. RESULTS The questionnaire was completed by 781 individuals (65.7%), of whom 31% indicated they would take an ECS test themselves. In addition, 55% agreed that ECS should be offered to all prospective parents. The most frequently selected argument in favor of ECS (47.2%) was that participants want to spare a child from a life with a severe hereditary disorder. The reason most often mentioned not to participate in ECS (48%) was that participants reported not having a hereditary disorder in the family. The majority preferred receiving individual test results above a couple-based disclosure method in which participants receive the carrier status results only when they are a carrier couple of the same disorder. Participants with religious beliefs were less likely to participate in ECS, whereas participants who were considering a (future) pregnancy were more likely to participate. CONCLUSION Our study demonstrates an overall positive attitude among participants of reproductive age in the general Dutch population towards preconception ECS. A striking misconception is that many of the participants believe that ECS is of interest only for those with a positive family history of one of the hereditary disorders. This finding emphasizes the importance of providing understandable, balanced information and education to the general public regarding the concepts of inheritance when presenting the option of carrier screening. Our results provide valuable insights that can be used in the debate about the responsible implementation of preconception ECS for AR disorders, including IEMs.
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Affiliation(s)
- Stephanie C M Nijmeijer
- Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Meibergdreef 9, Amsterdam, Netherlands.
| | - Thirsa Conijn
- Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Meibergdreef 9, Amsterdam, Netherlands.
| | - Phillis Lakeman
- Amsterdam UMC, University of Amsterdam, Clinical Genetics, Amsterdam Reproduction and Development Research Institute, Meibergdreef 9, Amsterdam, Netherlands.
| | - Lidewij Henneman
- Amsterdam UMC, Vrije Universiteit Amsterdam, Clinical Genetics, Amsterdam Reproduction and Development Research Institute, De Boelelaan 1117, Amsterdam, Netherlands.
| | - Frits A Wijburg
- Amsterdam UMC, University of Amsterdam, Pediatric Metabolic Diseases, Emma Children's Hospital and Amsterdam Lysosome Center "Sphinx", Meibergdreef 9, Amsterdam, Netherlands.
| | - Lotte Haverman
- Amsterdam UMC, University of Amsterdam, Psychosocial Department, Emma Children's Hospital, Meibergdreef 9, Amsterdam, Netherlands.
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Cornel MC, Bonham VL. Genomics for all in the 21st century? J Community Genet 2017; 8:249-251. [PMID: 28905227 PMCID: PMC5614891 DOI: 10.1007/s12687-017-0333-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2017] [Accepted: 09/03/2017] [Indexed: 01/08/2023] Open
Abstract
As the field of genomics enters the second decade after the completion of the International Human Genome Project, human genomics research is still far from reflective of the ancestral diversity found in global populations. This special issue of the Journal of Community Genetics brings together a global perspective on the need for researchers and health care professionals to support achievable milestones that will enhance global ancestral diversity in genomic research for the 21st century, and integrate the resulting knowledge into health care that benefits everyone. As the publications in this special issue illustrate, this will require focused community engagement, including often overlooked isolated populations, as well as meaningful integration of genomics and health services across the global landscape. With the advancement of sequencing technology and reduction in the cost, the time has come to address critical barriers.
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Affiliation(s)
- Martina C Cornel
- Department of Clinical Genetics and Amsterdam Public Health Research Institute, Section Community Genetics, VU University Medical Center, BS7, A527, Mail A509 APH, PO Box 7057, 1007 MB, Amsterdam, The Netherlands.
| | - Vence L Bonham
- Division of Intramural Research, Social and Behavioral Research Branch, National Institutes of Health, National Human Genome Research Institute, Bethesda, MD, USA
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Genetics in an isolated population like Finland: a different basis for genomic medicine? J Community Genet 2017; 8:319-326. [PMID: 28730583 PMCID: PMC5614886 DOI: 10.1007/s12687-017-0318-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2017] [Accepted: 06/29/2017] [Indexed: 11/24/2022] Open
Abstract
A unique genetic background in an isolated population like that of Finland offers special opportunities for genetic research as well as for applying the genetic developments to the health care. On the other hand, the different genetic background may require local attempts to develop diagnostics and treatment as the selection of diseases and mutations differs from that in the other populations. In this review, we describe the experiences of research and health care in this genetic isolate starting from the identification of specific monogenic diseases enriched in the Finnish population all the way to implementing the knowledge of the unique genetic background to genomic medicine at population level.
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