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PurposeMiscarriage, often resulting from a variety of genetic factors, is a common pregnancy outcome. Preconception genetic carrier screening (PGCS) identifies at-risk partners for newborn genetic disorders; however, PGCS panels currently lack miscarriage-related genes. In this study, we evaluated the potential impact of both known and candidate genes on prenatal lethality and the effectiveness of PGCS in diverse populations.MethodsWe analyzed 125,748 human exome sequences and mouse and human gene function databases. Our goals were to identify genes crucial for human fetal survival (lethal genes), to find variants not present in a homozygous state in healthy humans, and to estimate carrier rates of known and candidate lethal genes in various populations and ethnic groups.ResultsThis study identified 138 genes in which heterozygous lethal variants are present in the general population with a frequency of 0.5% or greater. Screening for these 138 genes could identify 4.6% (in the Finnish population) to 39.8% (in the East Asian population) of couples at risk of miscarriage. This explains the cause of pregnancy loss in approximately 1.1-10% of cases affected by biallelic lethal variants.ConclusionThis study has identified a set of genes and variants potentially associated with lethality across different ethnic backgrounds. The variation of these genes across ethnic groups underscores the need for a comprehensive, pan-ethnic PGCS panel that includes genes related to miscarriage.

Introduction: Diagnosing hemophilia B (HB) carrier status is important to manage bleeding in carriers and to prevent bleeding in potential offspring. Without a family history of hemophilia, diagnosing HB carrier status is challenging. Genetic testing is the gold‐standard, however it is reserved for individuals with a high suspicion of carrier status. Aims: To describe the distribution of activated partial thromboplastin time (aPTT) and factor IX coagulant (FIX:C) levels in HB carriers and assess the ratio of FIX:C to other Vitamin K dependent factors (FII:C, FVII:C, FX:C) as an indicator of HB carrier status. Methods: In this retrospective, single‐centre cohort study, subjects were included if they were obligate or genetically proven HB carriers. Distributions of aPTT and FIX:C were described and the relationship between FIX:C levels in carriers and severity of familial HB was analysed. Ratios of FIX:C to FII:C, FVII:C, FX:C were calculated. Results: Seventy‐two female HB carriers (median age: 34 years; IQR 24–43) were included. Median aPTT and FIX:C levels were 33.0 s [IQR 30.0–37.0] and 57 IU/dL [IQR 43–74]. Fifteen carriers (21%) had mild HB (FIX:C levels of 10–40 IU/dL). FIX:C levels trended higher in carriers of mild HB versus carriers of moderate/severe HB. In six carriers, the median ratio of FIX:C to other Vitamin K dependent factors was 0.44, with 92% of ratios being ≤ 0.75. Conclusion: aPTT and FIX:C levels were unreliable in diagnosing HB carrier status. A low ratio of FIX:C to other Vitamin K dependent factors may be a useful marker of HB carrier status. [ABSTRACT FROM AUTHOR]

In many countries, some form of genetic screening is offered to all or part of the population, either in the form of well-organized screening programs or in a less formalized way. Screening can be offered at different phases of life, such as preconception, prenatal, neonatal and later in life. Screening should only be offered if the advantages outweigh the disadvantages. Technical innovations in testing and treatment are driving changes in the field of prenatal and neonatal screening, where many jurisdictions have organized population-based screening programs. As a result, a greater number and wider range of conditions are being added to the programs, which can benefit couples' reproductive autonomy (preconception and prenatal screening) and improve early diagnosis to prevent irreversible health damage in children (neonatal screening) and in adults (cancer and cascade screening). While many developments in screening are technology-driven, citizens may also express a demand for innovation in screening, as was the case with non-invasive prenatal testing. Relatively new emerging issues for genetic screening, especially if testing is performed using DNA sequencing, relate to organization, data storage and interpretation, benefit–harm ratio and distributive justice, information provision and follow-up, all connected to acceptability in current healthcare systems. [ABSTRACT FROM AUTHOR]

Professional guidelines generally caution against carrier testing in minors, though prior research indicates parents request and providers sometimes facilitate testing for unaffected siblings of a child affected by a genetic disorder. We investigated the perspectives of genetic counselors in North America regarding carrier testing prior to adolescence. Practicing genetic counselors (n = 177) responded to an electronic survey assessing their willingness to facilitate testing in four hypothetical scenarios and their evaluation of parental motivations. Participants did not find parental arguments for testing persuasive, and most were unwilling to facilitate carrier testing in children. A significant interaction effect indicated the presence of nonactionable carrier‐associated health risks in adulthood made participants significantly less hesitant when the mode of inheritance was X‐linked. Participants considered parental motivations that center the child's interests as significantly more persuasive. This study suggests genetic counselors are resistant to carrier testing for familial disorders in young children and tend to align with current guidelines, yet they recognize nuance in various cases. Further investigation into this topic is warranted to support genetic counselors facing these requests as the ethics of pediatric carrier testing continues to be debated. [ABSTRACT FROM AUTHOR]

The primary goal of carrier screening is to identify asymptomatic individuals who carry variants associated with genetic diseases, to inform about the risk of having a child with a genetic disease. Carrier screening can be accomplished through different approaches including ethnicity-based screening, pan-ethnic screening, and expanded carrier screening (ECS), and the decision to pursue carrier screening is voluntary. ECS takes a broad approach by screening for a large number of genetic diseases irrespective of ethnic background, and ideally is performed prior to conception. ECS has many benefits, including that it does not depend on accuracy of reported ancestry, as well as its greater yield of information that can be used for reproductive decision-making. However, there are also many important limitations of ECS to consider, ranging from the yield of unexpected information, uncertainty about the phenotype of a particular disease for which an individual is a carrier, and greater downstream costs associated with further testing and genetic counseling. Detailed genetic counseling both prior to and after ECS is essential in order for patients to understand the breadth of this approach, potential and actual results, and limitations.

Reproductive genetic carrier screening provides information about people's chance of having children with certain genetic conditions. Severity of genetic conditions is an important criterion for their inclusion in carrier screening programmes. However, the concept of severity is conceptually complex and underspecified. We analyse why severity is an important concept in carrier screening and for reproductive decision‐making and show that assessments of severity can also have normative societal implications. While some genetic conditions are unambiguously associated with a high degree of suffering, there are many factors that contribute to how severe a condition is perceived to be, and perspectives will vary. Attempts to classify genetic conditions according to their severity tend to prioritise biomedical information at the expense of incorporating qualitative aspects of the impact of genetic conditions on people's lives. Further complexity arises because some genotypes can present with variable phenotypes and because some conditions are not always experienced in the same way by all people who have them. To acknowledge this complexity, we argue that an understanding of severity needs to distinguish between the severity of a genetic condition—requiring a generalised approach for purposes of policy development and programme design—and the severity of an instance of a genetic condition in a particular person. Families making reproductive decisions also require access to diverse experiences of the qualitative aspects of living with genetic conditions. As a result, reproductive carrier screening programmes must recognise and respond to the complexity inherent in determining the severity of genetic conditions. [ABSTRACT FROM AUTHOR]

BackgroundMassively parallel DNA sequencing, such as exome sequencing, has become a routine clinical procedure to identify pathogenic variants responsible for a patient's phenotype. Exome sequencing has the capability of reliably identifying inherited and de novo single-nucleotide variants, small insertions, and deletions. However, due to the use of 100-300-bp fragment reads, this platform is not well powered to sensitively identify moderate to large structural variants (SV), such as insertions, deletions, inversions, and translocations.MethodsTo overcome these limitations, we used next-generation mapping (NGM) to image high molecular weight double-stranded DNA molecules (megabase size) with fluorescent tags in nanochannel arrays for de novo genome assembly. We investigated the capacity of this NGM platform to identify pathogenic SV in a series of patients diagnosed with Duchenne muscular dystrophy (DMD), due to large deletions, insertion, and inversion involving the DMD gene.ResultsWe identified deletion, duplication, and inversion breakpoints within DMD. The sizes of deletions were in the range of 45-250 Kbp, whereas the one identified insertion was approximately 13 Kbp in size. This method refined the location of the break points within introns for cases with deletions compared to current polymerase chain reaction (PCR)-based clinical techniques. Heterozygous SV were detected in the known carrier mothers of the DMD patients, demonstrating the ability of the method to ascertain carrier status for large SV. The method was also able to identify a 5.1-Mbp inversion involving the DMD gene, previously identified by RNA sequencing.ConclusionsWe showed the ability of NGM technology to detect pathogenic structural variants otherwise missed by PCR-based techniques or chromosomal microarrays. NGM is poised to become a new tool in the clinical genetic diagnostic strategy and research due to its ability to sensitively identify large genomic variations.

Abstract: Despite numerous efforts to raise awareness, many hemophilia carriers and female persons with hemophilia (PWHs) remain undiagnosed. Between May 2021 and April 2023, we identified potential and obligate carriers of hemophilia A (HA) and hemophilia B (HB) by updating pedigrees of all PWHs followed at the Cliniques universitaires Saint-Luc, Brussels. Retrospective data on previously screened females were collected, including bleeding history, coagulation factor levels, and testing for the proband's pathogenic variant. In addition, a proactive approach involved sending 125 invitation letters to unscreened or incompletely screened individuals, through related PWHs. In pedigrees of 287 male PWHs (226 HA and 61 HB) and 7 female index patients from 236 families (184 HA and 52 HB), a total of 900 female individuals were identified. Of those, 454 were obligate and/or genetically proven carriers, and 118 were noncarriers. Genetic testing was conducted in 133 obligate, 237 potential, and 4 sporadic carriers, with 190 obligate and 328 potential carriers remaining untested. Among carriers with known factor levels (261/454), 42 HA (23.0%) and 23 HB carriers (29.5%) had a factor level <40 IU/dL. Carriers with a factor deficiency were screened on average 6 years earlier than other females (P = .034). This study, to our knowledge, represents the first systematic effort to identify potential carriers among families of all PWHs within a single center, emphasizing the challenges in comprehensive screening for female individuals genetically linked to one or more PWHs. Such initiatives are vital for achieving equitable access to hemophilia care for all potentially affected individuals, irrespective of gender. This trial was registered at www.ClinicalTrials.gov as #NCT05217992., (© 2024 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Objective: To increase patients' knowledge and access to genetic carrier screening (GCS) in a gynecologic setting by implementing a protocol to universally offer GCS education and screening to reproductive-age women during the preconception period at gynecologic-related visits., Design: The model for improvement quality improvement process model was used to guide this initiative., Local Problem/setting: Screening for genetic disease has been a part of preconception and genetic care for the past 50 years. Despite its longstanding presence and better accessibility and affordability of testing, there are no established protocols to universally offer screening to reproductive-age women during preconception care in the United States. The project was implemented at an outpatient gynecology clinic in Phoenix, Arizona., Participants: Fifty-one women ages 18 to 51 years., Intervention/measurements: A protocol was implemented to universally offer expanded GCS and health education to reproductive-age women during the preconception period at gynecologic-related visits. Women's responses to being offered GCS and the rationale for their response was documented on a spreadsheet., Results: All 51 participants were offered GCS during their visit. None of those 51 participants had any previous knowledge of GCS. All 51 participants declined GCS; reasons included the following: would consider it once closer to childbearing (53%), did not have any childbearing plans (31.3%), did not have any further childbearing plans (9.8%), or were not worried about the possibility of genetic disease (5.8%). None cited cost as a reason for declining GCS. After project completion, 3 of the 51 participants returned to the clinic to undergo GCS, and the clinic has adopted the intervention described here as its standard of care for patients who meet criteria for GCS., Conclusion: It is imperative to provide health education about GCS to women during preconception care so that they can make informed choices about family planning., (Copyright © 2024 AWHONN. Published by Elsevier Inc. All rights reserved.)

Prostate cancer (PrCa) is a largely heritable and polygenic disease. It is the most common cancer in people with prostates (PwPs) in Europe and the USA, including in PwPs of African descent. In the UK in 2020, 52% of all cancers were diagnosed at stage I or II. The National Health Service (NHS) long-term plan is to increase this to 75% by 2028, to reduce absolute incidence of late-stage disease. In the absence of a UK PrCa screening programme, we should explore how to identify those at increased risk of clinically significant PrCa.Incorporating genomics into the PrCa screening, diagnostic and treatment pathway has huge potential for transforming patient care. Genomics can increase efficiency of PrCa screening by focusing on those with genetic predisposition to cancer-which when combined with risk factors such as age and ethnicity, can be used for risk stratification in risk-based screening (RBS) programmes. The goal of RBS is to facilitate early diagnosis of clinically significant PrCa and reduce overdiagnosis/overtreatment in those unlikely to experience PrCa-related symptoms in their lifetime. Genetic testing can guide PrCa management, by identifying those at risk of lethal PrCa and enabling access to novel targeted therapies.PrCa is curable if diagnosed below stage III when most people do not experience symptoms. RBS using genetic profiling could be key here if we could show better survival outcomes (or reduction in cancer-specific mortality accounting for lead-time bias), in addition to more cost efficiency than age-based screening alone. Furthermore, PrCa outcomes in underserved communities could be optimised if genetic testing was accessible, minimising health disparities., Competing Interests: Competing interests: RAE has the following conflicts of interest to declare: Honoraria from Genitourinary Cancer Symposium, American Association of Clinical Oncology (GU-ASCO), Janssen, University of Chicago, Dana Farber Cancer Institute, USA, as a speaker; Educational honorarium from Bayer and Ipsen, member of external expert committee to Astra Zeneca, UK; She is a member of the Scientific Advisory Board (SAB) for Our Future Health; She undertakes private practice as a sole trader at The Royal Marsden NHS Foundation Trust and 90 Sloane Street SW1X 9PQ and 280 Kings Road SW3 4NX, London, UK. RH, EB, NP and ZK-J have no conflicts of interest to declare., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: This antenatal screening review will include reproductive screening evidence and approaches for pre-conception and post-conception, using first to third trimester screening opportunities., Methods: Focused antenatal screening peer-reviewed publications were evaluated and summarized., Results: Evidenced-based reproductive antenatal screening elements should be offered and discussed, with the pregnancy planning or pregnant person, during Preconception (genetic carrier screening for reproductive partners, personal and family (including reproductive partner) history review for increased genetic and pregnancy morbidity risks); First Trimester (fetal dating with ultrasound; fetal aneuploidy screening plus consideration for expanded fetal morbidity criteria, if appropriate; pregnant person preeclampsia screening; early fetal anatomy screening; early fetal cardiac screening); Second Trimester for standard fetal anatomy screening (18-22 weeks) including cardiac; pregnant person placental and cord pathology screening; pregnant person preterm birth screening with cervical length measurement); Third Trimester (fetal growth surveillance; continued preterm birth risk surveillance)., Conclusion: Antenatal reproductive screening has multiple elements, is complex, is time-consuming, and requires the use of pre- and post-testing counselling for most screening elements. The use of preconception and trimesters 'one to three' requires clear patient understanding and buy-in. Informed consent and knowledge transfer is a main goal for antenatal reproductive screening approaches., Competing Interests: Declaration of competing interest There are no conflicts by the author related to this manuscript content or topic., (Copyright © 2024. Published by Elsevier Ltd.)

Competing Interests: The authors declare that they have no conflict of interest.

Background and objectivesGiven the nature of FMR1 gene expansions, most biological mothers, and often multiple other family members of children with fragile X syndrome (FXS), will have a premutation, which may increase individual and family vulnerabilities. This article summarizes important gaps in knowledge and notes potential implications for pediatric providers with regard to developmental and medical risks for children and adolescents with an FMR1 premutation, including possible implications into adulthood.MethodsA structured electronic literature search was conducted on FMR1 pre- and full mutations, yielding a total of 306 articles examined. Of these, 116 focused primarily on the premutation and are included in this review.ResultsBased on the literature review, 5 topic areas are discussed: genetics and epidemiology; phenotypic characteristics of individuals with the premutation; implications for carrier parents of children with FXS; implications for the extended family; and implications for pediatricians.ConclusionsAlthough the premutation phenotype is typically less severe in clinical presentation than in FXS, premutation carriers are much more common and are therefore more likely to be seen in a typical pediatric practice. In addition, there is a wide range of medical, cognitive/developmental, and psychiatric associated features that individuals with a premutation are at increased risk for having, which underscores the importance of awareness on the part of pediatricians in identifying and monitoring premutation carriers and recognizing the impact this identification may have on family members.

The rapid development of genomic sequencing technologies has decreased the cost of genetic analysis to the extent that it seems plausible that genome-scale sequencing could have widespread availability in pediatric care. Genomic sequencing provides a powerful diagnostic modality for patients who manifest symptoms of monogenic disease and an opportunity to detect health conditions before their development. However, many technical, clinical, ethical, and societal challenges should be addressed before such technology is widely deployed in pediatric practice. This article provides an overview of the Newborn Sequencing in Genomic Medicine and Public Health Consortium, which is investigating the application of genome-scale sequencing in newborns for both diagnosis and screening.

Abstract Background Hemophilia carriers experience abnormal bleeding symptoms; however, a lack of awareness about this topic coupled with additional knowledge gaps and barriers leads to suboptimal care for this population. Objective The primary objective was to describe the current knowledge gaps and challenges from the perspective of both hemophilia carriers and their health care providers. Methods We carried out a mixed methods descriptive study with two population groups between September and December 2020. The hemophilia carrier perspective was obtained through both focus groups and questionnaires, whereas the health care providers perspective obtained via questionnaire sent to the Association of Hemophilia Care Directors of Canada and the Canadian Association of Nurses in Hemophilia Care. Focus groups were analyzed using descriptive thematic analysis and quantitative survey data was also analyzed. Results Eleven hemophilia carriers participated along with 19 health care providers (11 physicians, eight nurses). Hemophilia carrier focus group discussions identified four areas representing major challenges or knowledge gaps: (1) negative psychosocial impacts; (2) difficulty determining symptom significance; (3) need for self‐advocacy; (4) testing concerns. Survey results from both groups were aligned with the most important topics for ongoing education identified as information on abnormal bleeding symptoms, where to seek treatment, and considerations for heavy menstrual bleeding/menstruation. The majority of both study groups believe obligate or potential carriers should have factor levels checked regardless of age if symptoms of abnormal bleeding occur or before an invasive procedure. However, hemophilia carriers were significantly more in favor of genetic testing under the age of consent than health care providers in all scenarios evaluated.

Genetic carrier screening has been successfully used over the last decades to identify individuals at risk of transmitting specific DNA variants to their newborns, thus having an affected child. Traditional testing has been offered based on familial and/or ethnic backgrounds. The development of high-throughput technologies, such as next-generations sequencing, able to allow the study of large genomic regions in a time and cost-affordable way, has moved carrier screening toward a more comprehensive and extensive approach, i.e., expanded carrier screening (ECS). ECS simultaneously analyses several disease-related genes and better estimates individuals' carrier status. Indeed, it is not influenced by ethnicity and is not limited to a subset of mutations that may arise from poor information in some populations. Moreover, if couples carry out ECS before conceiving a baby, it allows them to obtain a complete estimation of their genetic risk and the possibility to make an informed decision regarding their reproductive life. Despite these advantages, some weakness still exists regarding, for example, the number of genes and the kind of diseases to be analyzed and the interpretation and communication of the obtained results. Once these points are fixed, it is expectable that ECS will become an ever more frequent practice in clinical settings. [ABSTRACT FROM AUTHOR]

Population-based genome wide association studies have identified a locus at 9p22.2 associated with ovarian cancer risk, which also modifies ovarian cancer risk in BRCA1 and BRCA2 mutation carriers. We conducted fine-scale mapping at 9p22.2 to identify potential causal variants in BRCA1 and BRCA2 mutation carriers. Genotype data were available for 15,252 (2,462 ovarian cancer cases) BRCA1 and 8,211 (631 ovarian cancer cases) BRCA2 mutation carriers. Following genotype imputation, ovarian cancer associations were assessed for 4,873 and 5,020 SNPs in BRCA1 and BRCA 2 mutation carriers respectively, within a retrospective cohort analytical framework. In BRCA1 mutation carriers one set of eight correlated candidate causal variants for ovarian cancer risk modification was identified (top SNP rs10124837, HR: 0.73, 95%CI: 0.68 to 0.79, p-value 2× 10-16). These variants were located up to 20 kb upstream of BNC2. In BRCA2 mutation carriers one region, up to 45 kb upstream of BNC2, and containing 100 correlated SNPs was identified as candidate causal (top SNP rs62543585, HR: 0.69, 95%CI: 0.59 to 0.80, p-value 1.0 × 10-6). The candidate causal in BRCA1 mutation carriers did not include the strongest associated variant at this locus in the general population. In sum, we identified a set of candidate causal variants in a region that encompasses the BNC2 transcription start site. The ovarian cancer association at 9p22.2 may be mediated by different variants in BRCA1 mutation carriers and in the general population. Thus, potentially different mechanisms may underlie ovarian cancer risk for mutation carriers and the general population.

Background: Hereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown. Methods: 1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing. Results: A total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing. Conclusion: This is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies. [ABSTRACT FROM AUTHOR]

Abstract Background Propionic acidemia (PA) is a severe monogenic disorder characterized by a deficiency of the mitochondrial protein propionyl-CoA carboxylase (PCC) enzyme, which is caused by mutations in the PCCA or PCCB gene. Preconception carrier screening could provide couples with meaningful information for their reproductive options; however, it is not widely performed in China. Case presentation This report describes a case of dizygotic twin siblings conceived by in vitro fertilization (IVF) and diagnosed with propionic acidemia (PA). Their parents had no history of PA. Tandem mass spectrometry and urine gas chromatography/mass spectrometry (GC/MS) of the twin siblings revealed markedly elevated propionyl carnitine (C3), C3/C2, and 3-hydroxypropionate in the plasma and urine. Whole-exome sequencing was performed for the twin siblings. A homozygous missense mutation, c.2002G > A (p.Gly668Arg) in PCCA, was identified in the twin siblings. Sanger sequencing confirmed the homozygous mutation in the twin siblings and identified their parents as heterozygous carriers of the c.2002G > A mutation in PCCA. Both neonates in this case died. This is an emotionally and financially devastating outcome that could have been avoided with genetic carrier screening before conception. If couples are screened before IVF and found to be silent carriers, then reproductive options (such as preimplantation genetic diagnosis or prenatal diagnosis) can be offered to achieve a healthy newborn. Conclusion This case is a reminder to infertile couples seeking IVF that it is beneficial to clarify whether they are silent carriers before undergoing IVF.

BackgroundHereditary cancer syndromes (HCS) are responsible for 5-10% of cancer cases. Genetic testing to identify pathogenic variants associated with cancer predisposition has not been routinely available in Vietnam. Consequently, the prevalence and genetic landscape of HCS remain unknown.Methods1165 Vietnamese individuals enrolled in genetic testing at our laboratory in 2020. We performed analysis of germline mutations in 17 high- and moderate- penetrance genes associated with HCS by next generation sequencing.ResultsA total of 41 pathogenic variants in 11 genes were detected in 3.2% individuals. The carrier frequency was 4.2% in people with family or personal history of cancer and 2.6% in those without history. The percentage of mutation carriers for hereditary colorectal cancer syndromes was 1.3% and for hereditary breast and ovarian cancer syndrome was 1.6%. BRCA1 and BRCA2 mutations were the most prevalent with the positive rate of 1.3% in the general cohort and 5.1% in breast or ovarian cancer patients. Most of BRCA1 mutations located at the BRCA C-terminus domains and the top recurrent mutation was NM_007294.3:c.5251C>T (p.Arg1751Ter). One novel variant NM_000038.6(APC):c.6665C>A (p.Pro2222His) was found in a breast cancer patient with a strong family history of cancer. A case study of hereditary cancer syndrome was illustrated to highlight the importance of genetic testing.ConclusionThis is the first largest analysis of carrier frequency and mutation spectrum of HCS in Vietnam. The findings demonstrate the clinical significance of multigene panel testing to identify carriers and their at-risk relatives for better cancer surveillance and management strategies.

Purpose: The objective of this study is to assess the carrier frequency and pathogenic variation of monogenetic diseases in a population of 114 subjects in Han Chinese from Hebei province who are undergoing assisted reproductive technology through the utilization of Expanded Carrier Screening (ECS)., Methods: The study utilized a panel consisting of 155 severe monogenic recessive genetic diseases for ECS. Next-generation sequencing technology was employed to identify specific variants associated with ECS in a cohort of 114 subjects from 97 couples, comprising 97 females and 17 male spouses., Results: A total of 114 individuals received ECS. The carrier rate of pathogenic genes in the enrolled population was 44.74% (51/114). Among the 97 females, the carrier rate of pathogenic genes was higher in those without assisted reproduction indicators than in those with assisted reproduction indicators (59.09% vs. 41.33%). However, the carrier rate of pathogenic genes in males without assisted reproductive technology was slightly lower than that with assisted reproductive technology (40% vs. 41.67%). Among both female and male participants, the carrier rate of pathogenic genes between individuals without indicators of assisted reproduction and those with such indicators was 55.55% vs. 41.38%. In 51 carriers, 72.55% (37/51) carried one genetic variant, 25.49% (13/51) carried two genetic variants, and 1.96% (1/51) carried three genetic variants. A total of 38 pathogenic genes were detected in this study, and GJB2 and MMACHC were most common. The carrier rates of the two genes were both 5.26% (6/114). A total of 55 variations were detected, and c.235delC was most frequently found. The carrier rate was 3.51% (4/114). The incidence of couples carrying the same pathogenic genes was 1.03% (1/97)., Conclusions: The findings elucidate the carrier rate of pathogenic genes among 155 severe monogenic recessive genetic diseases and underscore the significance of ECS as a preventive measure against congenital anomalies. When both partners carry the same genetic mutation for a monogenic disease, preventive strategies can be taken in offspring through preimplantation genetic testing (PGT), prenatal genetic testing, or the utilization of donor gametes. ECS is instrumental in assessing reproductive risk, guiding fertility-related decisions, and reducing the prevalence of monogenic recessive genetic disorders in subsequent generations., (© 2024. The Author(s).)

Background: Population-based expanded carrier screening (ECS) involves screening for multiple recessive diseases offered to all couples considering a pregnancy or during pregnancy. Previous research indicates that in some countries primary care professionals are perceived as suitable providers for ECS. However, little is known about their perspectives. We therefore aimed to explore primary care professionals' views on population-based ECS., Methods: Four online focus groups with 14 general practitioners (GPs) and 16 community midwives were conducted in the Netherlands., Results: Our findings highlight various perspectives on the desirability of population-based ECS. Participants agreed that ECS could enhance reproductive autonomy and thereby prevent suffering of the child and/or parents. However, they also raised several ethical, societal, and psychological concerns, including a tendency towards a perfect society, stigmatization, unequal access to screening and negative psychosocial consequences. Participants believed that provision of population-based ECS would be feasible if prerequisites regarding training and reimbursement for providers would be fulfilled. most GPs considered themselves less suitable or capable of providing ECS, in contrast to midwives who did consider themselves suitable. Nevertheless, participants believed that, if implemented, ECS should be offered in primary care or by public health services rather than as hospital-based specialized care, because they believed a primary care ECS offer increases access in terms of time and location., Conclusions: While participants believed that an ECS offer would be feasible, they questioned its desirability and priority. Studies on the desirability and feasibility of population-based ECS offered in primary care or public health settings are needed., (© The Author(s) 2023. Published by Oxford University Press.)

Competing Interests: Competing interests: None declared.

Background: We aimed to analyse the efficacy and added value of a targeted Israeli expanded carrier screening panel (IL-ECSP), beyond the first-tier test covered by the Israeli Ministry of Health (IMOH) and the second-tier covered by the Health Maintenance Organisations (HMOs)., Methods: A curated variant-based IL-ECSP, tailored to the uniquely diverse Israeli population, was offered at two tertiary hospitals and a major genetics laboratory. The panel includes 1487 variants in 357 autosomal recessive and X-linked genes., Results: We analysed 10 115 Israeli samples during an 18-month period. Of these, 6036 (59.7%) were tested as couples and 4079 (40.3%) were singles. Carriers were most frequently identified with mutations in the following genes: GJB2/GJB6 (1:22 allele frequency), CFTR (1:28), GBA (1:34), TYR (1:39), PAH (1:50), SMN1 (1:52) and HEXA (1:56). Of 3018 couples tested, 753 (25%) had no findings, in 1464 (48.5%) only one partner was a carrier, and in 733 (24.3%) both were carriers of different diseases. We identified 79 (2.6%) at-risk couples, where both partners are carriers of the same autosomal recessive condition, or the female carries an X-linked disease. Importantly, 48.1% of these would not have been detected by ethnically-based screening tests currently provided by the IMOH and HMOs, for example, variants in GBA, TYR, PAH and GJB2/GJB6 ., Conclusion: This is the largest cohort of targeted ECSP testing, tailored to the diverse Israeli population. The IL-ECSP expands the identification of couples at risk and empowers their reproductive choices. We recommend endorsing an expanded targeted panel to the National Genetic Carrier Screening programme., Competing Interests: Competing interests: DMB was involved in the design of the CarrierScan array and is entitled to certain royalties., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: Competing interests: None declared.

Background: Exploring the expression of X linked disorders like haemophilia A (HA) in females involves understanding the balance achieved through X chromosome inactivation (XCI). Skewed XCI (SXCI) may be involved in symptomatic HA carriers. We aimed to develop an approach for dissecting the specific cause of SXCI and verify its value in HA., Methods: A family involving three females (two symptomatic with severe/moderate HA: I.2, the mother, and II.1, the daughter; one asymptomatic: II.2) and two related affected males (I.1, the father and I.3, the maternal uncle) was studied. The genetic analysis included F8 mutational screening, multiplex ligation-dependent probe amplification, SNP microarray, whole exome sequencing (WES) and Sanger sequencing. XCI patterns were assessed in ectoderm/endoderm and mesoderm-derived tissues using AR -based and RP2 -based systems., Results: The comprehensive family analysis identifies I.2 female patient as a heterozygous carrier of F8 :p.(Ser1414Ter) excluding copy number variations. A consistent XCI pattern of 99.5% across various tissues was observed. A comprehensive filtering algorithm for WES data was designed, developed and applied to I.2. A Gly58Arg missense variant in VMA21 was revealed as the cause for SXCI.Each step of the variant filtering system takes advantage of publicly available genomic databases, non-SXCI controls and case-specific molecular data, and aligns with established concepts in the theoretical background of SXCI., Conclusion: This study acts as a proof of concept for our genomic filtering algorithm's clinical utility in analysing X linked disorders. Our findings clarify the molecular aspects of SXCI and improve genetic diagnostics and counselling for families with X linked diseases like HA., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening., Methods: This study was conducted among a total of 33 104 participants (16 610 females) from 12 clinical centers across China.Carrier status for 223 genes was analyzed using high-throughput sequencing and different PCR methods., Results: The overall combined carrier frequency was 55.58% for 197 autosomal genes and 1.84% for 26 X-linked genes in these participants.Among the 16 669 families, 874 at-risk couples (5.24%) were identified.Specifically, 584 couples (3.50%) were at risk for autosomal genes, 306(1.84%) for X-linked genes, and 16 for both autosomal and X-linked genes.The most frequently detected autosomal at-risk genes included GJB2(autosomal recessive deafness type 1A, 393 couples), HBA1/HBA2(α-thalassemia, 36 couples), PAH (phenylketonuria, 14 couples), and SMN1(spinal muscular atrophy, 14 couples).The most frequently detected X-linked at-risk genes were G6PD (G6PD deficiency, 236 couples), DMD (Duchenne muscular dystrophy, 23 couples), and FMR1(fragile X syndrome, 17 couples).After excluding GJB2 c.109G>A, the detection rate of at-risk couples was 3.91%(651/16 669), which was lowered to 1.72%(287/16 669) after further excluding G6PD.The theoretical incidence rate of severe monogenic birth defects was approximately 4.35‰(72.5/16 669).Screening for a battery of the top 22 most frequent genes in the at-risk couples could detect over 95% of at-risk couples, while screening for the top 54 genes further increased the detection rate to over 99%., Conclusion: This study reveals the carrier frequencies of 223 monogenic genetic disorders in the Chinese population and provides evidence for carrier screening strategy development and panel design tailored to the Chinese population.In carrier testing, genetic counseling for specific genes or gene variants can be challenging, and the couples need to be informed of these difficulties before testing and provided with options for not screening these genes or gene variants.

Aim: To determine the attitudes of pregnant couples toward carrier screening genomic tests., Methods: A validated 22-item questionnaire was offered in person by medical staff to pregnant women ≥32 weeks' gestation and their partners attending prenatal classes from May to July 2014. The questionnaire inquired about demographic data, interest in various forms of genetic carrier screening tests, and genetic literacy., Results: Of 497 respondents, 69% expressed strong interest in carrier screening. The interested respondents exhibited substantial support for screening for common (82%) or all known genetic diseases (79%), as well as for treatable (79%) and untreatable diseases (85%). The majority of respondents believed that genetic test results could provide them with a sense of security but also provoke anxiety and fear. They were aware that these results could affect their perspective on life, work, and the atmosphere within their family, and acknowledged the potential effect on their relationship with their partner. However, none of these concerns diminished their desire to learn about their carrier status. Respondents with higher genetic literacy exhibited greater interest in screening tests (P=0.006). More non-religious respondents compared with practicing religious respondents (P=0.002), and more respondents with higher education compared with those with lower education, expressed interest in screening (P=0.003)., Conclusion: Most respondents expressed considerable interest in receiving information about their carrier status through genetic tests.

Many commercial reproductive genetic carrier screening (RGCS) panels include genes associated with non-syndromic hearing loss (NSHL), however little is known about the general acceptability of their inclusion. Although some couples wish to avoid having a deaf child, there are effective interventions and supports available for deafness, and no consensus on whether it is appropriate to reproductively screen NSHL genes. This study explored views of people with personal experience of deafness regarding carrier screening for genes associated with NSHL. We interviewed 27 participants; 14 who identified as deaf and 13 hearing parents of a deaf child. Thematic analysis was undertaken on transcripts of interviews. The findings reveal the complexity of attitudes within these groups. Some vacillated between the wish to support prospective parents' reproductive autonomy and concerns about potential harms, especially the expression of negative messages about deafness and the potential loss of acceptance in society. While some participants felt carrier screening could help prospective parents to prepare for a deaf child, there was little support for reproductive screening and termination of pregnancy. Participants emphasized the need for accurate information about the lived experience of deafness. The majority felt deafness is not as severe as other conditions included in RGCS, and most do not consider deafness as a disability. People with personal experience of deafness have diverse attitudes towards RGCS for deafness informed by their own identify and experience, and many have concerns about how it should be discussed and implemented in a population wide RGCS program., (© 2023 The Authors. Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Expanded carrier screening (ECS) during prenatal care is an important test for identifying prospective parents' risk of inherited genetic diseases. However, barriers remain for effectively educating patients about ECS. Graphic medicine (i.e. comics) has grown as a mechanism for patient education. The purpose of this study was to explore attitudes and opinions of a comic to educate about ECS during prental care. Focus groups were conducted with pregnant women or women who recently gave birth (6 groups, n = 54). The participants were all female, 44.4% Latino/Hispanic, 16.7% Bi-Racial/Other, and 43.3% reporting some college education or high school degree. Most participants reported high enjoyment with the comic due to their relatability to the characters, simplicity of the story, description of medical outcomes in everyday terms and the exploration of multiple outcomes possible with ECS. In addition, participants reported that during pregnancy their reading habits increase as well as emotional reactions to the content and some participants stated they avoided reading information that may cause stress or anxiety. More research is needed to assess what features of the comic promote understanding and how that influences decisions and pre-test patient education for ECS. The use of graphic narratives may enable individuals to better understand medical information in general. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of this study is to evaluate the perspectives of infertility patients regarding genetic carrier screening, embryo sex selection, embryo research, and gene editing. Methods: An anonymous 32-question survey was distributed electronically to all patients who seen at a single academic fertility center for at least one visit between June 2018 and September 2019. Survey questions evaluated patient perspectives on genetic carrier screening, embryo sex selection, embryo research, and gene editing. Results: There were 1460 survey responses (32.0% response rate). There were significant differences in the proportion of respondents receiving genetic carrier screening between racial groups, 73.1% of White, 45.5% of Black, 49.4% of Hispanic, and 62.8% of Asian respondents. The likelihood of having genetic carrier screening was also significantly influenced by respondent income, insurance status, and religion. Religion significantly influenced the acceptance of embryonic research and embryonic sex selection. While only 8.9% felt that genetically modifying embryos for physical traits should be allowed, 74.1% felt that genetic modification to correct disease should be allowed. Conclusion: Racial, religious, and socioeconomic factors significantly impacted respondents' likelihood to have genetic carrier screening and views on embryo sex selection, embryo research, and gene editing. These findings highlight the importance of tailoring genetic counseling to the individual, acknowledging individual and cultural differences in agreement with genetic testing and emerging genetic therapies. [ABSTRACT FROM AUTHOR]

Individuals with the short variant of the serotonin transporter linked polymorphic region gene are more susceptible than individuals homozygous for the long allele to the effects of stressful life events on risk for internalizing and externalizing problems. We tested whether individual differences in coping style explained this increased risk for problem behavior among youth who were at both genetic and environmental risk. Participants included 279 children, ages 8-11, from the Children's Experiences and Development Study. Caregivers and teachers reported on children's internalizing and externalizing symptoms, and caregivers and children on children's exposure to harsh parenting and parental warmth in middle childhood, and traumatic events. Children reported how frequently they used various coping strategies. Results revealed that short/short homozygotes had higher levels of internalizing problems compared with long allele carriers and that short allele carriers had higher levels of externalizing problems compared with long/long homozygotes under conditions of high cumulative risk. Moreover, among children who were homozygous for the short allele, those who had more cumulative risk indicators less frequently used distraction coping strategies, which partly explained why they had higher levels of internalizing problems. Coping strategies did not significantly mediate Gene × Environment effects on externalizing symptoms.

Methods for detecting the genomic signatures of natural selection have been heavily studied, and they have been successful in identifying many selective sweeps. For most of these sweeps, the favored allele remains unknown, making it difficult to distinguish carriers of the sweep from non-carriers. In an ongoing selective sweep, carriers of the favored allele are likely to contain a future most recent common ancestor. Therefore, identifying them may prove useful in predicting the evolutionary trajectory--for example, in contexts involving drug-resistant pathogen strains or cancer subclones. The main contribution of this paper is the development and analysis of a new statistic, the Haplotype Allele Frequency (HAF) score. The HAF score, assigned to individual haplotypes in a sample, naturally captures many of the properties shared by haplotypes carrying a favored allele. We provide a theoretical framework for computing expected HAF scores under different evolutionary scenarios, and we validate the theoretical predictions with simulations. As an application of HAF score computations, we develop an algorithm (PreCIOSS: Predicting Carriers of Ongoing Selective Sweeps) to identify carriers of the favored allele in selective sweeps, and we demonstrate its power on simulations of both hard and soft sweeps, as well as on data from well-known sweeps in human populations.

ObjectivesThe possibility of newborn screening for fragile X syndrome is complicated by the potential for identifying premutation carriers. Although knowing the child's carrier status has potential benefits, the possibility of late-onset disorders in carrier children and their parents raises concerns about whether such information would be distressing to parents and potentially more harmful than helpful. This study sought to answer this question by offering voluntary fragile X screening to new parents and returning results for both the full mutation and premutation FMR1 gene expansions. We tested the assumption that such information could lead to adverse mental health outcomes or decision regret. We also wanted to know if child age and spousal support were associated with the outcomes of interest.MethodsEighteen mothers of screen-positive infants with the premutation and 15 comparison mothers completed a battery of assessments of maternal anxiety, postpartum depression, stress, family quality of life, decision regret, and spousal support. The study was longitudinal, with an average of 3 assessments per mother.ResultsThe premutation group was not statistically different from the comparison group on measures of anxiety, depression, stress, or quality of life. A subset of mothers experienced clinically significant anxiety and decision regret, but factors associated with these outcomes could not be identified. Greater spousal support was generally associated with more positive outcomes.ConclusionsAlthough we did not find evidence of significant adverse events, disclosure of newborn carrier status remains an important consideration in newborn screening policy.

We utilized a sample of 299 adult females aged between 19 and 86 years, carrying fragile X mental retardation (FMR1) alleles with small CCG expansions ranging from 50 to 141 repeats to analyse the relationships between psychological symptoms as assessed by the Symptom Checklist-90-Revised (SCL-90-R) and the size of the CGG repeat in the FMR1 gene. There were highly significant (negative) correlations between the size of the CGG repeat and a great majority of SCL-90-R subscale scores and all the global indices, suggesting that carriers of premutations in the mid-size CGG repeat range may be at greatest risk for the development of psychiatric disorder.

Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.

Carriers of the apolipoprotein E (APOE) ε4 allele, the major genetic risk for Alzheimer's disease (AD), harbor an increased load of β-amyloid (Aβ) plaque burden that is felt to be a major instigator of AD development. Data has suggested that lifestyle factors may reduce AD risk by directly mitigating Aβ pathology, which could be particularly beneficial in APOE ε4 carriers. We therefore examined the interaction between lifetime cognitive activity and the APOE ε4 allele in relation to brain Aβ burden. We obtained measures of lifetime cognitive activity in 118 cognitively normal human individuals (mean age: 76.13 ± 5.56 years, 70 women) using a validated questionnaire that included measures over early, middle, and current age epochs. Hierarchical regression models (adjusted for age, gender, and years of education) were conducted to examine effects of APOE ε4 carrier status, lifetime cognitive activity, and the interaction of the two factors with cortical Aβ deposition, quantified using [11C] Pittsburgh-compound-B (PIB)-PET. As expected, the ε4 carriers exhibited higher PIB retention compared with noncarriers. Lifetime cognitive activity moderated the APOE genotype effect such that cortical PIB retention was diminished in ε4 carriers that reported higher cognitive activity over the life course. The findings suggest that greater lifetime cognitive activity may forestall AD pathology, specifically in genetically susceptible individuals. The effect could imply that cognitive training promotes increased neural efficiency that might retard the lifelong neurally mediated deposition of Aβ.

Background: Cystic fibrosis (CF) carrier screening should be offered to people planning a pregnancy or in early pregnancy, according to current recommendations. However, research indicates rates of offering CF carrier screening are low. Health professionals (HPs) play an important role in offering population carrier screening. Aims: To determine the opinions, knowledge and practice patterns of HPs with regard to the routine offering of population carrier screening for CF. Materials and Methods: Five key informant interviews informed the development of an online questionnaire which was distributed to a select group of HPs involved in prenatal care in Victoria, Australia. Results: Of the participants who completed the questionnaire (n = 87), 35.6% reported offering CF carrier screening to all patients attending for preconception or early pregnancy consultations. High referrers of CF carrier screening were more likely to be female, work in the private sector, in metropolitan areas and specialise as an obstetrician. High referrers demonstrated a greater level of knowledge of CF and carrier screening than low referrers (t = −3.779, P < 0.001). Low referrers perceived more barriers to offering carrier screening than high referrers (t = 2.125, P = 0.037). Low referrers were more likely to perceive lack of community awareness and HP knowledge as a barrier to offering CF carrier screening, compared to high referrers, who were more likely to perceive time constraints as a barrier. Conclusions: To promote routine offering of population CF carrier screening, resources are needed to improve knowledge and provide clinical support thereby reducing perceived barriers. [ABSTRACT FROM AUTHOR]

Screening for rare diseases first began more than 50 years ago with neonatal bloodspot screening (NBS) for phenylketonuria, and carrier screening for Tay-Sachs disease, sickle cell anaemia and β-thalassaemia. NBS's primary aim is health gain for children, while carrier screening enables autonomous reproductive choice. While screening can be beneficial, it also has the potential to cause harm and thus decisions are needed on whether a specific screening is worthwhile. These decisions are usually based on screening principles and criteria. Technological developments, both treatment driven and test driven, have led to expansions in neonatal screening and carrier screening. This article demonstrates how the dynamics and expansions in NBS and carrier screening have challenged four well-known screening criteria (treatment, test, target population and programme evaluation), and the decision-making based on them. We show that shifting perspectives on screening criteria for NBS as well as carrier screening lead to converging debates in these separate fields. For example, the child is traditionally considered to be the beneficiary in NBS, but the family and society can also benefit. Vice versa, carrier screening may be driven by disease prevention, rather than reproductive autonomy, raising cross-disciplinary questions regarding potential beneficiaries and which diseases to include. In addition, the stakeholders from these separate fields vary: Globally NBS is often governed as a public health programme while carrier screening is usually available via medical professionals. The article concludes with a call for an exchange of vision and knowledge among all stakeholders of both fields to attune the dynamics of screening. [ABSTRACT FROM AUTHOR]

Genetic carrier screening has been successfully used over the last decades to identify individuals at risk of transmitting specific DNA variants to their newborns, thus having an affected child. Traditional testing has been offered based on familial and/or ethnic backgrounds. The development of high-throughput technologies, such as next-generations sequencing, able to allow the study of large genomic regions in a time and cost-affordable way, has moved carrier screening toward a more comprehensive and extensive approach, i.e., expanded carrier screening (ECS). ECS simultaneously analyses several disease-related genes and better estimates individuals’ carrier status. Indeed, it is not influenced by ethnicity and is not limited to a subset of mutations that may arise from poor information in some populations. Moreover, if couples carry out ECS before conceiving a baby, it allows them to obtain a complete estimation of their genetic risk and the possibility to make an informed decision regarding their reproductive life. Despite these advantages, some weakness still exists regarding, for example, the number of genes and the kind of diseases to be analyzed and the interpretation and communication of the obtained results. Once these points are fixed, it is expectable that ECS will become an ever more frequent practice in clinical settings.

BackgroundWe examined forensic serum toxicology and pharmacogenomics data from a woman on codeine shortly before she caused a motor vehicle accident.MethodsA woman driving erratically collided with a parked car of a highway seriously injuring 2 men working to repair the parked vehicle. The woman tested positive for codeine, acetaminophen and barbital. She had been taking these medications for 20 years due to migraine headache. Serum toxicology and genotype analysis for cytochrome P450, UDP glucuronosyltransferase, and other metabolizing enzymes were measured.ResultsThe woman was tried and convicted of driving under the influence resulting in bodily harm and was sentenced to 6 years. Toxicology results on peripheral blood showed a total and free codeine of 840 and 348 μg/L, respectively, and total morphine of 20 μg/L (17, 3, and 0 μg/L for morphine-3-glucuronide, morphine-6-glucuronide, and free morphine, respectively). She was heterozygous for CYP 2D6 *2/*4 (extensive/poor metabolism) and heterozygous for UGT 2B7 *1/*2 (extensive/ultra-rapid metabolism). The woman was also taking fluoxetine and bupropion which are strong inhibitors of CYP 2D6.ConclusionsBased on her genotype and phenotype and reports by the arresting officer, we suggest that the subject in question was not intoxicated by opiates at the time of her motor vehicle accident and may have been falsely incarcerated.

Previous studies examining communication of BRCA1/2 results with relatives and family uptake of BRCA1/2 testing have sampled from predominantly white, high SES cohorts ascertained solely from tertiary care centers. No studies have focused on family communication and testing among relatives of diverse BRCA1/2 carriers. We conducted structured interviews with 73 BRCA1/2 carriers identified at a public hospital and a tertiary cancer center. We asked participants if each first- and second-degree relative was aware of their BRCA1/2 results and whether or not each relative had tested. Generalized estimating equations identified rates and predictors of family communication and testing. Participants disclosed their test results to 73 % of 606 eligible relatives and 31 % of 514 eligible relatives tested. Communication and testing rates were similar for relatives of participants from the public hospital and the tertiary cancer center. Hospital site was not a significant predictor of either result disclosure or relative uptake of testing. African American and Asian/Pacific Islander participants were significantly less likely to disclose their results to their relatives; relatives of African American participants were significantly less likely to test. Addressing these disparities will require further research into the best ways to facilitate family communication and counsel at-risk relatives of racially and socioeconomically diverse BRCA1/2 mutation carriers.

BackgroundGermline mutations in BRCA1 and BRCA2 (BRCA1/2) are related to an increased lifetime risk of developing breast and ovarian cancer. Although risk-reducing salpingo-oophorectomy reduces the risk of both cancers, loss of fertility is a major concern. A recent study suggested an association between BRCA1 mutation and occult primary ovarian insufficiency. The objective of the current study was to determine whether BRCA1/2 mutation carriers have an earlier onset of natural menopause compared with unaffected women.MethodsWhite carriers of the BRCA1/2 gene (n = 382) were identified within the Breast Cancer Risk Program Registry at the University of California at San Francisco and compared with non-clinic-based white women in northern California (n = 765). The 2 groups were compared with regard to median age at the time of natural menopause before and after adjustment for known risk factors, and the role of smoking within each group was examined using the Kaplan-Meier approach for unadjusted analyses and Cox proportional hazards regression analyses for adjusted analyses.ResultsThe median age at the time of natural menopause in the BRCA1/2 carriers was significantly younger than among the unaffected sample (50 years vs 53 years; P < .001). The unadjusted hazard ratio for natural menopause when comparing BRCA1/2 carriers with unaffected women was 4.06 (95% confidence interval, 3.03-5.45) and was 3.98 (95% confidence interval, 2.87-5.53) after adjusting for smoking, parity, and oral contraceptive use. For BRCA1/2 carriers who were current heavy smokers (smoking ≥ 20 cigarettes/day), the median age at natural menopause was 46 years versus 49 years for nonsmokers (P = .027).ConclusionsThe BRCA1/2 mutation was associated with a significantly earlier age at natural menopause, and heavy smoking compounded this risk. Because the relationship between menopause and the end of natural fertility is considered to be fixed, these findings suggest the risk of earlier infertility among BRCA1/2 carriers.

Timely diagnosis of recessive single-gene diseases in patients is of the utmost importance for the implementation of the available methods of disease prevention or specific symptomatic therapy when the disease has already developed. Furthermore, an important link in the prevention and monitoring of the likelihood of appearance of recessive monogenic diseases are various possibilities of genetic testing that can detect carriers, who are most often healthy individuals but can transmit the genetic change to offspring. This review article presents the latest findings related to the definition, frequency, and diagnosis of recessive monogenic diseases, including diagnostic genetic testing, carrier testing, population screening, and extended genomic carrier screening. [ABSTRACT FROM AUTHOR]

Background: Townes-Brocks syndrome (TBS) is a rare genetic disorder characterised by multiple malformations. Due to its phenotypic heterogeneity and rarity, diagnosis and recognition of TBS can be challenging and there has been a lack of investigation of patients with atypical TBS in large cohorts and delineation of their phenotypic characteristics., Methods: We screened SALL1 and DACT1 variants using next-generation sequencing in the China Deafness Genetics Consortium (CDGC) cohort enrolling 20 666 unrelated hearing loss (HL) cases. Comprehensive clinical evaluations were conducted on seven members from a three-generation TBS family. Combining data from previously reported cases, we also provided a landscape of phenotypes and genotypes of patients with TBS., Results: We identified five novel and two reported pathogenic/likely pathogenic (P/LP) SALL1 variants from seven families. Audiological features in patients differed in severity and binaural asymmetry. Moreover, previously undocumented malformations in the middle and inner ear were detected in one patient. By comprehensive clinical evaluations, we further provide evidence for the causal relationship between SALL1 variation and certain endocrine abnormalities. Penetrance analysis within familial contexts revealed incomplete penetrance among first-generation patients with TBS and a higher disease burden among their affected offspring., Conclusion: This study presents the first insight of genetic screening for patients with TBS in a large HL cohort. We broadened the phenotypic-genotypic spectrum of TBS and our results supported an underestimated prevalence of TBS. Due to the rarity and phenotypic heterogeneity of rare diseases, broader spectrum molecular tests, especially whole genome sequencing, can improve the situation of underdiagnosis and provide effective recommendations for clinical management., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Due to the high rate of consanguineous marriages in Oman, there is a correspondingly high prevalence of hereditary blood disorders, particularly sickle cell disease and β-thalassaemia. This article proposes the possibility of implementing mandatory premarital carrier screening for blood disorders in Oman, while giving due consideration to potential social and cultural obstacles. Although the implementation of such legislation would require collaboration between different sectors and may negatively affect the autonomy of certain individuals, mandatory premarital screening would help to alleviate the burden of hereditary blood disorders on the national healthcare system, as well as reduce avoidable suffering among carriers and their families.

Introduction: Cystic fibrosis is an autosomal recessive genetic disease classified as a high-cost orphan disease. Objective: To determine the cost-effectiveness ratio of the diagnostic test of CFTR gene sequencing for asymptomatic family carriers in the first, second and third degree of consanguinity. Materials and method: A systematic search was carried out evaluating operative characteristics of the diagnostic test and decision tree models in cost-effectiveness studies. A decision tree model was elaborated having as a unit of analysis the prevention of future conceptions. The costs of the disease were obtained from the highcost report of the Ministry of Health of Colombia. The costs of the test were referenced by national laboratories. We carried out a deterministic and probabilistic sensitivity analysis with a third-payer perspective and a one-year horizon. Results: An ICER of $ 5 694,27 was obtained, as an incremental cost for obtaining a 10,89% more probability of avoiding the birth of a child with cystic fibrosis by a sifted partner. For family members in the second and third grades, an ICER of $ 21 848,78 and $ 63 033,19 was found. It was evidenced when applying the GDP per capita; this technology was cost-effective in 39%, 61,18% and 74,36% for 1, 2 and 3 GDP per capita in relatives of first degree of consanguinity. Conclusions: The genetic test for carrier detection for cystic fibrosis is cost effective depending on the threshold of availability to pay, the assumptions and limitations established in the model. [ABSTRACT FROM AUTHOR]

Introduction: The Israeli population, encompassing 9 million citizens, is comprised of diverse communities. The Ministry of Health genetic screening program for reproductive purposes was introduced in 2013. This program is mainly aimed at severe incurable diseases with high rates of infant and childhood morbidity and/or mortality, with a carrier frequency of at least 1:60 and/or a disease frequency of 1 in 15 000 live births. In this paper, we present the results of the national genetic carrier-screening program implementation.Material and Methods: Data acquisition for this study was performed by retrospectively searching Ministry of Health database, which includes the reports of 18 genetic laboratories performing genetic screening tests.Results: During 2015-2017, a total of 919 820 carrier-screening genetic tests were executed. The overall number rose by 14.9% over these years. For about two-thirds of the presented disorders, carrier frequency was within the expected range. A decrease of 57% was noted in the observed number of patients with spinal muscular atrophy born during 2014-2017, compared with the expected rate. Familial dysautonomia, Canavan and Tay-Sachs diseases yielded a very low prevalence.Conclusions: Our results highlight the impact of a national genetic carrier-screening program. Couples at risk of an affected fetus mostly choose to perform preconception or prenatal diagnosis and to act accordingly. Our country has several characteristics enabling us to achieve this success, including considerable rates of endogamy and consanguineous marriages, increased frequency of founder mutations, and high fertility rates. In addition, wide accessibility of the tests and good compliance of the population must be noted. Still, raising the awareness and continuing education of population and caregivers about the importance and efficiency of carrier screening remains an important issue. Finally, expanding the existing tests into a uniform, wide genetic panel seems to be the next goal. [ABSTRACT FROM AUTHOR]