Carrier Screening Research Articles

P-508 Management of incidental findings after preconception expanded carrier screening: identifying genetic predispositions to cancer and metabolic conditions in 8010 screened ART patients

Abstract Study question How do individuals and fertility clinics navigate incidental findings from Expanded Carrier Screening (ECS) in reproductive decision-making? Summary answer Incidental ECS findings prompted varied responses from patients and gamete donors, influencing diverse reproductive choices and underscoring the pivotal role of pre-test genetic counseling. What is known already ECS aims to assess reproductive risk in the general population for specific autosomal recessive and X-linked conditions. These manifest in infancy or early childhood and impact life expectancy or the quality of life. ECS results may guide interventions to avoid affected pregnancies, such as the implementation of preimplantation genetic testing of embryos (PGT-M). Additionally, ECS has the potential to uncover incidental findings with significant health implications, such as an elevated cancer risk or diagnosis. However, the lack of comprehensive reporting guidelines necessitates meticulous analysis to ensure effective clinical guidance for these individual findings. Study design, size, duration This retrospective descriptive study assessed the results of ECS tests performed in 5475 patients and 2535 oocyte and semen donors from four different fertility clinics between July 2017 and December 2023. ECS reports with incidental findings in the ATM, FH or LDLR genes were identified and further examined. We calculated individual and reproductive risks for affected individuals and recorded the subsequent clinical management pertaining to each case. Participants/materials, setting, methods Pre-test counselling was offered to both patients and gamete donors before consenting to ECS. Testing was outsourced to an external genetics laboratory using a panel of 309 genes analyzed through next generation sequencing and complementary molecular techniques. The laboratory reported pathogenic and likely pathogenic variants that were subsequently manually reviewed by an internal genetics committee. Personal and reproductive risks were assessed for each case and genetic counseling was provided in a subsequent meeting. Main results and the role of chance Genetic variants in ATM, FH, or LDLR genes were reported in 134 out of 8010 individuals undergoing ECS (1.67%). Among these, 108 variants were identified in patients: 53.7% (n = 58) in ATM, 19.4% in FH (n = 21), and 26.8% (n = 29) in LDLR. Out of the variants identified as incidental findings, 20/108 were actionable and eligible for PGT-M: 19 were associated with an increased risk for breast cancer and 1 for renal cancer. After being informed of the findings and their implications, 7/20 couples opted to revoke treatment as, according to internal policies, PGT-M was mandatory in such cases; 6/20 couples chose to undergo double gamete donation; 6/20 couples opted for PGT-M. Patients with pathogenic variants in LDLR linked to autosomal dominant inheritance for familial hypercholesterolemia (20/108, 18.5%), received follow-up guidelines and family genetic counseling. Pathogenic variants in ATM, FH, and LDLR were also identified in 26 gamete donors (24 oocyte donors and 2 sperm donors). Following internal review, 14 of these variants were considered incidental findings with an increased risk for breast cancer (13/14) or familial hypercholesterolemia (1/14), leading to the exclusion of these potential donors from the donation program. Limitations, reasons for caution The reproductive handling of incidental findings in our population relies on subjective decisions by the internal genetics committee, which may evolve with scientific advancements and recommendations from professional societies. Follow-up data on long-term reproductive outcomes are lacking. Wider implications of the findings This study reveals the diverse reproductive decisions made in response to incidental findings, underscoring the importance of pre-test genetic counseling. Our findings also highlight the subsequent impact on fertility programs, which may lead to the exclusion of gamete donors or patients choosing to revoke treatment. Trial registration number Not Applicable

P-551 Application of simultaneous PGT-M/PGT-A using whole genome sequencing and haplotyping for monogenetic disorders, multiple variants, low penetrance, and de novo disorders

Abstract Study question Is the concurrent use of high-resolution PGT-A and genome-wide haplotyping with disease-specific assays for PGT-M effective in an unselected patient population at-risk for monogenetic disorders? Summary answer PGT-A/PGT-M is an effective treatment for couples/patients burdened with genetic diseases, that provides optimal family planning, prevents vertical transmission, and reduces personal and societal encumbrance What is known already Societal awareness of genetic testing expanded the use of carrier screening, diagnostic genetic tests, and higher in vitro fertilization (IVF) utilization has increased demand for preimplantation genetic testing for monogenetic disorders (PGT-M), as an alternative to invasive prenatal tests. The scope of PGT-M testing expands beyond common severe childhood disorders, to include serious and mild late onset disorders, cancer predisposition, variants of unknown significance, de novo mutations, and variants in multiple genes. This highlights novel ethical dilemmas, necessitating adjustment of generic genome wide approaches to complement, or eventually replace, targeted disease-specific PGT-M assays. Study design, size, duration This is a retrospective study of 359 couples at-risk for monogenetic disorders referred to the CReATe Fertility Centre, Toronto, Canada. Our objective was to evaluate the efficiency of concurrent use of genome wide haplotyping and disease specific assays for PGT-M and high resolution PGT-A in an unselected patient population at risk for monogenetic disorders, multiple and de novo variants, low penetrance and variants of unknown significance. Participants/materials, setting, methods All patients received comprehensive genetic counselling. For each couple/patient, DNA from gamete providers, related family member/s and whole-genome amplified (WGA)DNA from a single trophectoderm(TE) biopsy were analyzed. Whole-genome SNP-array (Karyomapping, Illumina, CA) and STR-analysis were used to obtain parental haplotypes and Sanger-sequencing was used for direct variant analysis. PGT-A was performed using Illumina platform(NextSeq 550). NxClinical (BioDiscovery) and BlueFuse Multi(Illumina) software were used for data analysis. Main results and the role of chance 1826 embryos, from 235 IVF cycles were analyzed for 88 unique genes (14 cancer predisposing, 42 autosomal recessive and 32 dominant genes) and a total of 282 unique variants. The most frequent genes tested were BRCA1/2 -21% of all cases, followed by HBB-8.7%, CFTR-8.7% and CYP21A2-8.7%. PGT-M for 11 cases was done for a de novo variant detected in a sibling and in 2 cases for a parental mosaic variant. Multiple genes and VUS were analyzed in 12 and 6 cases, respectively. PGT-A analysis showed 31.6% aneuploidy, 9.6% mosaicism and 58.8% euploidy. Genome wide haplotyping was used for euploid and mosaic embryos with an average case call rate of 95%, and average case Allele Drop Out (ADO) rate of 2.7%. Recombination events in 3% of cases prevented assignment of haplotype. Direct mutation testing was obtained for all samples and was 100% concordant with the predicted haplotypes. In cases with no predicted haplotype, direct testing established the PGT-M diagnosis. The distribution for both recessive and dominant disorders was in Mendelian order. To date 66 live births confirmed the results from PGT-M diagnosis. Limitations, reasons for caution Ethical considerations and extensive genetic counselling are prerequisites for PGT-A/M testing implementation. Simultaneous screening for embryo aneuploidy and monogenetic disorders optimizes patient treatment and family planning, but may not be available in all jurisdictions. Although the data was collected prospectively, retrospective design is a limitation. Wider implications of the findings Simultaneous PGT-A and PGT-M with direct variant testing provides optimal embryo prioritization for transfer and significantly reduces time to a healthy pregnancy in couples at risk for inherited disorders. Karyomapping is effective for generic haplotyping, with a low risk of undetected recombination events in the genomic region of interest. Trial registration number not applicable

Managing risks for genetic conditions in donor sperm treatment: current practices in Belgian fertility clinics

Research questionHow do fertility clinics in Belgium manage risks for genetic conditions in donor sperm treatment? DesignAn electronic questionnaire was distributed to all fertility clinics in Belgium in June 2023, focusing on treatments with anonymous sperm donors from 2018 to 2022. Responses from 15 clinics were analysed anonymously using IBM SPSS statistics. ResultsAll clinics assessed donor risks, including a personal and family history, conventional karyotyping and (for 83.3% of the clinics) carrier screening for common autosomal recessive conditions. For recipients, 58.3% of the clinics relied only on a personal and family history. Despite efforts, the suspicion or detection of genetic conditions in donor sperm treatment was prevalent, with 9.4 adverse events reported per 100 children born. When adverse events occurred, most clinics (58.3%) would not inform the donor if no additional genetic testing was needed. Around 1 in 4 (26.7%) clinics always informed recipients about an adverse event possibly related to their donor. An equal number (26.7%) categorically ruled out the use of spermatozoa from a donor after an adverse event was traced back to his DNA, and 53.3% would not consider using the donor when the adverse event was not genetically confirmed. For the other clinics, deciding when to disclose new genetic risk information or when to allow the use of a donor linked to an adverse event was a complex matter involving different considerations. ConclusionAlthough suspected or detected genetic conditions linked to donor treatments were common, there was wide variation in how Belgian clinics prevented and managed these situations.

Strategic Implementation of Fragile X Carrier Screening in China: A Focused Pilot Study

Fragile X syndrome (FXS) is the leading genetic cause of intellectual disability and autism spectrum disorders. Female premutation carriers exhibit no obvious symptoms during reproductive age, but the premutation allele can expand to full mutation when transmitted to the fetus.. Given the relatively low prevalence but large population, the distinct healthcare system, the middle-income economic status, and low awareness among public and medical professionals, the optimal genetic screening strategy remains unknown. We conducted a pilot study of Fragile X carrier screening in China, involving 22,245 pregnant women and women with childbearing intentions, divided into control and pilot groups. The prevalence of Fragile X carriers in the control group was 1/850, similar to East Asian populations. Strikingly, the prevalence of Fragile X carriers in the pilot group was 1/356, which can be attributed to extensive medical training, participant education, and rigorous genetic counseling and testing protocols. Cost-effectiveness analyses of four strategies—no screening, population-based screening, targeted screening, and our pilot screening—indicated that our pilot screening was the most cost-effective option. A follow-up survey revealed that 55% of respondents reported undergoing screening due to their family history. We have successfully established a standardized system, addressing the challenges of low prevalence, limited awareness, and genetic testing complexities. Our study provides practical recommendations for implementing Fragile X carrier screening in China.

Shortcomings of ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish ancestry

PurposeCarrier screening identifies reproductive risk for autosomal recessive and X-linked genetic conditions. Currently, some medical society guidelines continue to recommend ethnicity-based carrier screening for conditions associated with Ashkenazi Jewish (AJ) ancestry. We assessed the utility and limitations of these guidelines in a large, ethnically and genetically diverse cohort of genotyped individuals. MethodsWe characterized the self-reported ethnicity and genetic ancestry of over 110,000 consenting research participants identified as heterozygous for pathogenic variants associated with 15 autosomal recessive conditions recommended by the American College of Obstetricians and Gynecologists for screening in individuals of AJ descent. ResultsOut of 7.2 million research participants, 116,517 research participants were identified as heterozygous for pathogenic variants associated with 15 conditions evaluated. The majority (54.9%) of heterozygotes did not report qualifying ethnicity under American College of Obstetricians and Gynecologists ethnicity-based screening guidelines. Approximately half (51.3%) of all individuals heterozygous for pathogenic variants in genes associated with 1 or more conditions recommended to be screened exclusively in individuals of AJ descent had <20% computed AJ ancestry. ConclusionEthnicity-based carrier screening leads to the under detection of heterozygotes and associated reproductive risk for conditions historically associated with AJ ancestry.

NanoRanger enables rapid single-base-pair resolution of genomic disorders

Delineating base-resolution breakpoints of complex rearrangements is crucial for an accurate clinical understanding of pathogenic variants and for carrier screening within family networks or the broader population. However, despite advances in genetic testing using short-read sequencing (SRS), this task remains costly and challenging. This study addresses the challenges of resolving missing disease-causing breakpoints in complex genomic disorders with suspected homozygous rearrangements by employing multiple long-read sequencing (LRS) strategies, including a novel and efficient strategy named nanopore-based rapid acquisition of neighboring genomic regions (NanoRanger). NanoRanger does not require large amounts of ultrahigh-molecular-weight DNA and stands out for its ease of use and rapid acquisition of large genomic regions of interest with deep coverage. We describe a cohort of 16 familial cases, each harboring homozygous rearrangements that defied breakpoint determination by SRS and optical genome mapping (OGM). NanoRanger identified the breakpoints with single-base-pair resolution, enabling accurate determination of the carrier status of unaffected family members as well as the founder nature of these genomic lesions and their frequency in the local population. The resolved breakpoints revealed that repetitive DNA, gene regulatory elements, and transcription activity contribute to genome instability in these novel recessive rearrangements. Our data suggest that NanoRanger greatly improves the success rate of resolving base-resolution breakpoints of complex genomic disorders and expands access to LRS for the benefit of patients with Mendelian disorders. M.L. is supported by KAUST Baseline Award no. BAS/1/1080-01-01 and KAUST Research Translation Fund Award no. REI/1/4742-01.

The Uptake of Partner Participation in Sequential Preconception Carrier Screening

Introduction: Carrier screening that is performed in the preconception period allows for couples at risk for having children affected with certain single gene (Mendelian) conditions to be identified. This is the most optimal timeframe to perform such screening. Most obstetric providers utilize a sequential process in which the patient first undergoes screening and their partner is only offered testing if the initial results reveal that the first is a carrier for one or more autosomal recessive (AR) deleterious variants. If the partner fails to undergo screening, the couple cannot obtain meaningful and actionable risk information for future or current pregnancies. In this study, we sought to assess the frequency of completed carrier screening risk assessment among individuals and couples who were undergoing preconception screening at two prenatal screening programs staffed by genetic counselors and geneticists. Materials and Methods: We reviewed the screening outcomes for individuals and couples who presented for preconception carrier screening from January 1, 2020 through December 30, 2021 at Insight Medical Genetics and the clinical genetics program at Northwestern Medicine. All individuals received pretest genetic counseling prior to screening and posttest counseling after results were available. We evaluated individuals who were found to be a carrier of at least one deleterious variant and whether the partner of that person underwent carrier screening, and, if so, which type of screening. Results: 548 patients who identified as women underwent preconception carrier screening during the study period, along with 3 men presenting for initial screening. These screens consisted of a panel containing primarily autosomal recessive conditions with a few X-linked conditions. 247 individuals (45.1%) were positive for at least one pathogenic variant; of these, 244 (98.8%) were variants in genes associated with autosomal recessive conditions. A total of 219 partners (88.7%) underwent carrier screening, including the 3 female partners of the men who initiated carrier screening. Of note, 4 of the patients who underwent carrier screening reported not having a partner at the time of screening; accordingly, the partners who underwent screening represent 89.8% of individuals eligible for partner screening following an initial positive result. Of the 219 partners who underwent carrier screening, 201 (91.8%) chose a carrier screening panel of 150+ conditions, while 18 chose a more limited panel that included the gene(s) of relevance based on their partner’s results, with or without additional genes relevant to their learned/self-identified ethnicity or race. Conclusions: Approximately 10% of couples presenting for preconception genetic counseling and carrier screening found to be at potential risk for a child with an autosomal recessive condition did not obtain the requisite information to fully assess their risk of having an affected child. It is possible that the frequency of couples who do not obtain complete and actionable screening information is even higher when carrier screening is provided without the assistance of certified genetic counselors or geneticists. Recently, cell free DNA-based maternal screening has been introduced that assesses the risk for a limited number of genetic conditions in the fetus that may not require assessment of the partner. Nonetheless, providers must communicate to their patients that meaningful risk information can only be obtained when the partner undergoes screening in cases where the initial member of the couple is found to be a carrier of at least one autosomal recessive condition. Laboratories and professional societies need to develop effective educational outreach to patients and providers alike to improve the screening process for couples who want to determine if they are at risk to have a child with an inherited condition.

Reproductive genetic carrier screening in pregnancy: improving health outcomes and expanding access.

Reproductive genetic carrier screening (RGCS) serves to screen couples for their risk of having children affected by monogenic conditions. The included conditions are mostly autosomal recessive or X-linked with infantile orearly-childhood onset. Cystic fibrosis, spinal muscular atrophy, and hemoglobinopathies are now recommended by the American College of Obstetricians and Gynecologists (ACOG) for universal screening. Recommendations for further RGCS remain ethnicity based. The American College of Medical Genetics and Genomics and the National Society of Genetic Counselors in recent years have recommended universal expanded-panel RGCS and moving towards a more equitable approach. ACOG guidelines state that offering RGCS is an acceptable option, however it has not provided clear guidance on standard of care. Positive results on RGCS can significantly impact reproductive plans for couples, including pursuing invitro fertilization with preimplantation genetic testing, prenatal genetic testing, specific fetal orneonatal treatment, or adoption. RGCS is a superior approach compared to ethnicity-based carrier screening and moves away from single race-based medical practice. We urge the obstetrics and gynecology societies to adopt the guidelines for RGCS put forward by multiple societies and help reduce systemic inequalities in medicine in our new genetic age. Having national societies such as ACOG and theSociety for Maternal-Fetal Medicine officially recommend and endorse RGCS would bolster insurance coverage and financial support by employers for RGCS. The future of comprehensive reproductive care in the age of genomic medicine entails expanding access so patients and families can make the reproductive options that best fit their needs.

Application of whole exome sequencing in carrier screening for high-risk families without probands.

This study aimed to screen the genetic etiology for the high-risk families including those with an adverse pregnancy history, a history of consanguineous marriages, or a history of genetic diseases, but lack of proband via whole exome sequencing (WES). 128 individuals from high-risk family were tested by WES. The candidate variants were analyzed according to the ACMG criteria to screen the potential carriers. At-risk couples (ARCs) who harbored the same causative gene were provided with precise fertility guidance to avoid the birth of children with birth defects. The total detection rate was 36.72%, with pathogenic/likely pathogenic (P/LP) variants found in 47 individuals, and variants of uncertain significance (VUS) were found in 34. Among couples with adverse pregnancy history: P/LP variants were found in 38 individuals, and VUS were found in 26, for a detection rate of 34.55%; among members of family history of genetic disease or consanguineous marriages: P/LP variants were found in nine individuals, and VUS were found in 8, for a detection rate of 50.00%. Otherwise, we detected 19 ARCs who both carried P/LP variants in the same gene, with a theoretical offspring prevalence of up to 7.42%. In the absence of probands, carrier screening using WES can provide an efficient tool for screening the molecular etiology of high-risk families.

Carrier screening for 223 monogenic diseases in Chinese population: a multi-center study in 33 104 individuals

To investigate the epidemiological characteristics and mutation spectrum of monogenic diseases in Chinese population through a large-scale, multicenter carrier screening. 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. 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%. 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.

Expert consensus over genetic counseling for carrier screening of Spinal muscular atrophy

Spinal muscular atrophy (SMA), an autosomal recessive neuromuscular disease with a carrier frequency of 1/60 ~ 1/40, is characterized by severe clinical symptoms, high mortality rate, and expensive treatment costs. Carrier screening is of paramount importance to detect high-risk couples, and therefore to reduce the occurrence of SMA. In China, SMA carrier screening has become widespread, though there is still a lack of genetic counseling expertise. This article has focused on the current challenges for SMA carrier screening, including the screening methods, target population, screening procedures, and pre-/post-testing counseling. The aim is to standardize its application and counseling in the clinical practice.

Expert consensus on the genetic counseling for Dystrophinopathies

Dystrophinopathies caused by variants of DMD gene are a group of muscular diseases including Duchenne muscular dystrophy, Becker muscular dystrophy, and DMD-associated dilated cardiomyopathy. With the advancement of genetic testing techniques and wider implementation of genetic screening, especially the expanded carrier screening, more and more individuals carrying DMD gene variants have been identified, whereas the genetic counseling capacity is relatively insufficient. Currently there is still a lack of professional norms for genetic counseling on dystrophinopathies. In this consensus, the main points to be covered in the pre- and post-test consultation have been discussed, with an aim to provide genetic counseling guidance for the disease diagnosis, treatment, and family reproduction.

Investigation of genotype-phenotype and familial features of Turkish dystrophinopathy patients.

Duchenne muscular dystrophy (DMD) and Becker muscular dystrophy (BMD) are X-linked recessive allelic muscle diseases caused by dystrophin gene mutations. Eight hundred thirty-seven patients admitted between 1997 and 2022 were included in the study. Two hundred twenty patients were analyzed by multiplex PCR (mPCR) alone. Five hundred ninety-five patients were investigated by multiplex ligation-dependent probe amplification (MLPA), and 54 patients were examined by sequencing. Deletion was detected in 60% (132/220) of the cases in the mPCR group only and in 58.3% (347/595) of the cases with MLPA analysis. The rates of deletion and duplication were 87.7% and 12.3%, respectively, in the MLPA analysis. Single exon deletions were the most common mutation type. The introns 43-55 (81.8%) and exons 2-21 (13.1%) regions were detected as hot spots in deletions. It was determined that 89% of the mutations were suitable for exon skipping therapy. The reading frame rule did not hold in 7.6% of D/BMD cases (17/224). We detected twenty-five pathogenic/likely pathogenic variants in sequencing, five of which were novel variants. Nonsense mutation was the most common small mutation (44%). 21% of DMD patients were familial. We detected germline mosaicism in four families (4.3%) in the large rearrangement group and one gonosomal mosaicism in a family with a nonsense mutation. This is the largest study examining genotype and phenotype data in Turkish D/BMD families investigated by MLPA analysis. The reading frame hypothesis is not valid in all cases. Sharing the genotype and phenotype characteristics of these cases in the literature will shed light on the molecular structure of DMD and guide gene therapy research. In genetic counseling, carrier screening in the family and possible gonadal mosaicism should be emphasized.

The psychosocial impact of prostate cancer screening for BRCA1 and BRCA2 carriers.

To report the long-term outcomes from a longitudinal psychosocial study that forms part of the 'Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted Screening in men at higher genetic risk and controls' (IMPACT) study. The IMPACT study is a multi-national study of targeted prostate cancer (PrCa) screening in individuals with a known germline pathogenic variant (GPV) in either the BReast CAncer gene 1 (BRCA1) or the BReast CAncer gene 2 (BRCA2). Participants enrolled in the IMPACT study were invited to complete a psychosocial questionnaire prior to each annual screening visit for a minimum of 5 years. The questionnaire included questions on sociodemographics and the following measures: Hospital Anxiety and Depression Scale, Impact of Event Scale, 36-item Short-Form Health Survey, Memorial Anxiety Scale for PrCa, Cancer Worry Scale, risk perception and knowledge. A total of 760 participants completed questionnaires: 207 participants with GPV in BRCA1, 265 with GPV in BRCA2 and 288 controls (non-carriers from families with a known GPV). We found no evidence of clinically concerning levels of general or cancer-specific distress or poor health-related quality of life in the cohort as a whole. Individuals in the control group had significantly less worry about PrCa compared with the carriers; however, all mean scores were low and within reported general population norms, where available. BRCA2 carriers with previously high prostate-specific antigen (PSA) levels experience a small but significant increase in PrCa anxiety (P = 0.01) and PSA-specific anxiety (P < 0.001). Cancer risk perceptions reflected information provided during genetic counselling and participants had good levels of knowledge, although this declined over time. This is the first study to report the longitudinal psychosocial impact of a targeted PrCa screening programme for BRCA1 and BRCA2 carriers. The results reassure that an annual PSA-based screening programme does not have an adverse impact on psychosocial health or health-related quality of life in these higher-risk individuals. These results are important as more PrCa screening is targeted to higher-risk groups.

The Use of Expanded Carrier Screening in Reproductive Medicine: Scientific Impact Paper No. 74.

Expanded carrier screening (ECS) is a genetic screening test carried out by analysing a blood sample. This screen can be used to detect whether the individual unknowingly carries gene variants associated with common genetic conditions, such as cystic fibrosis, that may be passed on to their children. It is typically performed in reproductive medicine for those who are considering having a family either naturally or via fertility treatment. Many donor sperm and egg banks, particularly in the USA and Europe, also perform blanket ECS testing on all their prospective sperm and egg donors. ECS is not currently routine practice in the UK, but a growing number of patients are requesting it before treatment. All of us carry gene variants of some sort that may cause autosomal recessive disease in their children if their partner or donor also carry a variant in the same gene. An autosomal recessive disease means two copies of an abnormal gene must be present in order for the disease or trait (such as cystic fibrosis or sickle cell disease) to develop. One copy of the variant means the person is a carrier but does not have the condition. Two copies, i.e. from the mother and father, means the child has a 25% chance of having the genetic disease. Carrying a gene variant does not mean that the individual would necessarily have any symptoms of the disease or any features of the condition. Genetic tests for specific conditions are currently available either before or during pregnancy for prospective parents who have a family or personal history of a genetic condition, or for those from ethnic backgrounds where certain conditions - such as haemoglobinopathies (blood disorders) - are common, prompting referral to a clinical genetics department. Expanded carrier screens may test for more than 100 genetic conditions. The list of conditions screened for is called a panel. Common panels are 250 or 600 genes. Not all expanded carrier screens that are available analyse the same genes. Some may test for genes that do not cause serious disease, or cause diseases that occur in later life; others test for genes that cause severe conditions in childhood. There is no agreement as to which panel of genes should be tested for in an ECS. Understanding the screening that is being offered, and the meaning of any results, is complicated and requires support from appropriately trained professionals to best inform the prospective parent or parents.

Contribution of mammography to breast cancer detection among pathogenic germline BRCA carriers by age and mutated gene.

10615 Background: Healthy carriers of pathogenic germline BRCA 1/2 (gBRCA) may choose between risk reducing mastectomy and intensive screening surveillance. Current international guidelines recommend both annual breast MRI and annual mammography. The aim of this study was to investigate the added contribution of annual mammography in gBRCA carriers to the annual breast MRI. Methods: A retrospective study from 2 large centers comprising gBRCA carriers who were diagnosed with breast cancer between 2000-2022 and were aware of their gBRCA status prior breast cancer diagnosis. Collected data included age at diagnosis, mutated gene and mode of breast cancer diagnosis (MRI, mammography, ultrasound [US], or other means [including clinical or incidental findings]). Data on pregnancy and breastfeeding at the time of breast cancer diagnosis were also collected. Differences in the mode of diagnosis were analyzed by age (≤40y vs. &gt;40y) and mutated gene (BRCA1 vs. BRCA2). Results: The cohort included 200 gBRCA carries: 134 (67%) BRCA1, 62 (31%) BRCA2 and 4 (2%) with both BRCA1 and BRCA2 mutations. The median age at the time of breast cancer diagnosis was 41 (24-88). Most cancers (68%) were diagnosed by MRI, followed by mammography (14.5%), US (7%) and other means (10.5%). While MRI was the most common diagnosis modality in both age groups, the distribution of mode of diagnosis was significantly different in younger women (≤40y) where breast cancer detection was more commonly by US or following clinical findings, compared to older women, p&lt; 0.001 (see Table). Five women were pregnant and 9 women were breastfeeding at the time of breast cancer diagnosis, all age 40 or younger. Four (80%) of pregnant carriers and 5 (55.6%) of breastfeeding carriers were diagnosed by US. There was no difference in mode of diagnosis between BRCA1 to BRCA2 carriers, p=0.974. There were only 16 women under age 30 that were diagnosed with breast cancer, 2 (12.5%) of whom were diagnosed with mammography. Conclusions: MRI is the most common modality for breast cancer diagnosis in gBRCA carriers who were aware if there gBRCA prior breast cancer diagnosis. Annual mammography also has a meaningful role in this population. We did not identify a subgroup in which it could be omitted. The increased utility of US among younger women is attributed to reduced utilization of MRI/mammography during pregnancy and breastfeeding. This finding strengthens the role of US screening in gBRCA carriers who are not eligible for other methods of imaging. [Table: see text]

The Influences of Medical Students' Consent to Participate in Thalassemia Research

An effective way of learning about thalassemia, a complex public health issue with multiple perspectives, is through participating in research. This study used an inductive approach to presume the influencing factors of students' consent to participate in thalassemia research voluntarily. Nested in the preliminary stage of a research series on thalassemia, this study used a consecutive sampling to recruit 140 medical undergraduates. Their knowledge, experience, and attitude to thalassemia and the perception of self-quality life were assessed using self-administered questionnaires. Blood samples were drawn for carrier screening. Students' GPAs were collected from faculty records. Of 140 participants, only 123 had at least heard of thalassemia, and their data was used in the analysis. Most participants had fairly good but incomplete knowledge of inheritance patterns, antenatal screening, and thalassemia management. Premarital screening was known and received the most positive attitudes from participants. Inductively, academic performance and carrier status curiosity were presumed to influence students' consent to participate. With the limitation of an inductive approach, further study with a specific design is needed to closely investigate student perspectives on research and their drives to get involved.

Beyond severity: utility as a criterion for setting the scope of RGCS.

Reproductive genetic carrier screening (RGCS) allows prospective parents to identify and act upon their chances of having a child with a genetic condition. In deciding which genetic conditions to include in RGCS, severity is often used as a criterion. However, the concept is inherently complex, subjective and multidimensional, and determinations of severity will remain intractably contested. We propose the concept of utility as a criterion for setting the scope of RGCS, and put forward two central arguments for doing so. First, utility is a more appropriate and effective concept as it responds to context and makes an explicit connection between the purpose of RGCS and the value of information obtained for that purpose: namely, to facilitate reproductive decision-making. Utility comprises both clinical and personal utility, and varies according to the availability and accessibility of reproductive options, including pre-implantation genetic testing, prenatal genetic diagnosis, and termination of pregnancy. Second, there are ethical reasons for preferring utility over severity. Utility is a property of the information gleaned from RGCS, while severity is a property of a genetic condition or of an instance of this condition in a person. While consideration of the severity of genetic conditions is not lost when focusing on utility, the need to rely on value judgements regarding the quality of life of people who live with genetic conditions is circumvented. Therefore, utility should replace severity as justification for the inclusion of genetic conditions in RGCS programmes.

Comprehensive analysis of thalassemia alleles (CATSA) based on third-generation sequencing is a comprehensive and accurate approach for neonatal thalassemia screening

Thalassemia is one of the most common and damaging monogenic diseases in the world. It is caused by pathogenic variants of α- and/or β-globin genes, which disrupt the balance of these two protein chains and leads to α-thalassemia or β-thalassemia, respectively. Patients with α-thalassemia or β-thalassemia could exhibit a severe phenotype, with no simple and effective treatment. A three-tiered strategy of carrier screening, prenatal diagnosis and newborn screening has been established in China for the prevention and control of thalassemia, of which the first two parts have been studied thoroughly. The implementation of neonatal thalassemia screening is lagging, and the effectiveness of various screening programs has not yet been demonstrated. In this study, hemoglobin capillary electrophoresis (CE), hotspot testing method, and third-generation sequencing (TGS) were used in the variant detection of 2000 newborn samples, to assess the efficacy of these methods in neonatal thalassemia screening. Compared with CE (249, 12.45 %) and hotspot analysis (424, 21.2 %), CATSA detected the largest number of thalassemia variants (535, 26.75 %), which included 24 hotspot variants, increased copy number of α-globin gene, rare pathogenic variants, and three unreported potentially disease-causing variants. More importantly, CATSA directly determined the cis–trans relationship of variants in three newborns, which greatly shortens the clinical diagnosis time of thalassemia. CATSA showed a great advantage over other genetic tests and could become the most powerful technical support for the three-tiered prevention and control strategy of thalassemia.

Creatine Kinase-MM/Proto-oncogene Tyrosine-Protein Kinase Receptor as a Sensitive Indicator for Duchenne Muscular Dystrophy Carriers.

Duchenne muscular dystrophy (DMD), a lethal X-linked recessive genetic disease, is characterized by progressive muscle wasting which will lead to premature death by cardiorespiratory complications in their late twenties. And 2.5-19% DMD carriers that also suffer from skeletal muscle damage or dilated cardiomyopathy when diagnosed as soon as possible is meaningful for prenatal diagnosis and advance warning for self-health. The current DMD carrier screening mainly relies on detecting serum creatine kinase activity, covering only 50-70% DMD carriers which will cause many false negatives and require the discovery of highly effective biomarker and simple detection procedure for DMD carriers. In this article, we have compiled a comprehensive summary of all documented biomarkers associated with DMD and categorized them based on their expression patterns. We specifically pinpointed novel DMD biomarkers, previously unreported in DMD carriers, and conducted further investigations to explore their potential. Compared to creatine kinase activity alone in DMD carriers, creatine kinase-MM can improve the specificity from 73 to 81%. And our investigation revealed another promising protein: proto-oncogene tyrosine-protein kinase receptor (RET). When combined with creatine kinase-MM (creatine kinase-MM/RET ratio), it significantly enhances the specificity (from 81 to 83%) and sensitivity (from71.4 to 93%) of detecting DMD carriers in serum. Moreover, we successfully devised an efficient method for extracting RET from dried blood spots. This breakthrough allowed us to detect both creatine kinase-MM and RET using dried blood spots without compromising the detection rate.