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At least 19 recordsLinked to original sources
PubMed2025

A dataset of estimated heterozygous individual and carrier couple frequencies for pan-ancestry carrier screening.

The data described in this publication supported the development and evaluation of pan-ancestry reproductive carrier screening panels for autosomal recessive (AR) and X-linked (XL) conditions. Raw data included combined sets of DNA variants in 1,350 AR/XL genes obtained from the ClinVar and gnomAD databases. The dataset enabled calculations of positive yield for individuals and couples across both ancestry-specific and pan-ancestry, optimised "Goldilocks"-ranked gene panels, addressing population-specific variations in the frequencies of heterozygous individuals and carrier couples. The positive yield analysis offered a performance metric for carrier screening panels, facilitating the modeling of screening performance for panels of varying sizes and composition and providing resources for optimizing panel content to ensure equity across underrepresented genetic ancestries The dataset can support ongoing research into the equitable application of carrier screening and offers significant reuse potential for refining population genetic screening practices, validating computational models, and developing frameworks to update carrier screening panels in alignment with evolving genomic data, including in underrepresented and minority populations.

Carrier screening↗
PubMed2025

Optimizing gene panels for equitable reproductive carrier screening: The Goldilocks approach.

PURPOSE: Professional organizations recommend pan-ancestry carrier screening for autosomal recessive and X-linked conditions. Advances in DNA sequencing have allowed the analysis of hundreds of genes; however, the optimal number of genes for carrier screening remains unclear. The American College of Medical Genetics and Genomics (ACMG) has proposed a tiered approach recommending screening for 113 genes. METHODS: We analyzed ClinVar and gnomAD v4.1.0, for genes associated with serious autosomal recessive and X-linked conditions and modeled screening performance across panels of varying compositions and sizes in diverse genetic ancestries. We also reevaluated the ACMG gene list using the updated gnomAD data. RESULTS: We identified potential inconsistencies in the ACMG gene lists, particularly in the carrier test performance (defined as a positive yield) for underrepresented genetic ancestry groups. Modeling of the population data for 1310 genes revealed that the screening of 152, 248, 531, and 725 genes achieved 90%, 95%, 99%, and 99.7% positive yields, respectively, in couples. Real-world data from the screening of more than 60,000 couples were used to validate the model. CONCLUSION: Our methodology optimizes the gene content of carrier screening panels for diverse ancestry groups, provides a mechanism for continually updating guidelines, ensures consistency with genomic population data, and improves equity across populations.

Humans↗
PubMed2025

Nationwide carrier screening for congenital adrenal hyperplasia: integrated approach of CYP21A2 pathogenic variant genotyping and comprehensive large gene deletion analysis.

BACKGROUND: Congenital Adrenal Hyperplasia (CAH) due to 21-hydroxylase deficiency (21-OHD CAH) is an autosomal recessive disorder resulting from pathogenic variants in the CYP21A2 gene. The disorder exhibits variable clinical severity, with the classical form manifesting as salt-wasting crisis in neonates, while inducing ambiguous genitalia in females and precocious puberty in males through simple virilization. Identifying at-risk couples during the preconception stage holds significance for optimizing reproductive choices. METHODS: This study included 204 unrelated preconception individuals undergoing carrier screening. A robust molecular approach was devised for rapid detection of nine prevalent CYP21A2 pathogenic variants, utilizing Amplification-Refractory Mutation System (ARMS) PCR and mass spectrometry (MS) genotyping. Complementary quantitative real-time PCR (qPCR) and PCR-based Restriction Fragment Length Polymorphism (PCR-based RFLP) assays were employed for comprehensive gene deletion analysis. The concordance of pathogenic variant detection between ARMS-PCR and MS, as well as the consistency observed in molecular insights from qPCR and PCR-based RFLP, fortified the accuracy of our methodologies. RESULTS: Our combined method could detect common pathogenic variants and large gene deletions with high concordance between ARMS-PCR, MS genotyping, qPCR, and PCR-based RFLP assays. Remarkably, two carriers exhibited significant large-scale deletions, while another manifested a carrier state due to minor-scale gene conversion. The estimated carrier frequency in our cohort using these methods was approximately 1 in 65 individuals. CONCLUSIONS: The methods used for 21-OHD CAH carrier screening offer a reliable, swift, and cost-effective approach for detecting common pathogenic variants and large deletions. Despite some limitations, such as the inability to detect all rare mutations, the techniques provide a practical solution for carrier screening, with an estimated carrier frequency of 1 in 65 in our study population. These findings support the potential adoption of these methods in national carrier screening programs, offering a practical balance between efficiency and affordability.

Humans↗
PubMed2026

Psychologically informed reminder messages for promoting BRCA1/2 carrier screening: evidence from a large-scale population-based study.

Psychologically Informed Reminder Messages (PIRMs) may promote health-behavior change, but their impact on preventive genetic screening is unclear. Due to low adherence to a screening program, Clalit Health Services initiated an intervention to encourage BRCA1/2 carrier screening in July 2022. This observational study assesses the effectiveness of the intervention in encouraging screening and its spillover effect on related healthcare utilization, focusing on Ashkenazi Jewish females aged 25-50 with no relevant cancer history. Patients were randomly assigned to receive one of five PIRMs. Four PIRMs utilized different psychological strategies, while the fifth served as a control. The effectiveness of the intervention on screening adherence was assessed using a regression discontinuity analysis. A Cox regression assessed the effectiveness of the four PIRMs compared to the control. Spillover effects on healthcare utilization were evaluated using logistic regressions. The intervention showed a positive correlation with increased adherence to screening (β = 0.37, 95% CI: 0.01-0.72). The "Barrier Remover" PIRM emphasized ease (hazards ratio = 1.09, 95% CI: 1.02-1.16), while the "Health Control" PIRM focused on autonomy (hazards ratio = 1.07, 95% CI: 1.01-1.14), both indicating greater effectiveness than the control. The findings suggest a positive short-term spillover effect of the "Health Control" PIRM on healthcare utilization compared to the control (odds ratio = 1.16, 95% CI: 1.04-1.29). PIRMs effectively increased BRCA1/2 carrier screening adherence, demonstrating a scalable, low-cost intervention to improve preventive healthcare uptake. The effect varied by the psychological strategies, highlighting the potential of tailored behavioral interventions to enhance public health.

Humans↗
PubMed2025

Rethinking the pathogenicity of intragenic DMD duplications detected by carrier screening: High prevalence of nontandem duplications revealed by long-read sequencing.

PURPOSE: The pathogenicity of intragenic duplications depends on their structural configuration. Tandem duplications often disrupt reading frames and cause gene loss of function, whereas interspersed (nontandem) duplications are largely benign. When the configuration cannot be determined, current guidelines presume a tandem structure, leading to some laboratories automatically classifying such variants as likely pathogenic or pathogenic. This study evaluates the validity of this presumption for DMD, in patients with and without clinical indications of dystrophinopathy. METHODS: We performed high-coverage long-read genome sequencing on 15 patients with intragenic DMD duplications. A total of 4 patients had clinically indicated dystrophinopathy testing, whereas in the remaining 11 patients, the duplications were detected without clear indications of dystrophinopathy (eg, through carrier screening). RESULTS: All 4 patients with clinical indications had tandem duplications. In contrast, 64% (7/11) of the cases without such indications had interspersed duplications, with 4 subsequently reclassified as likely benign, 2 (likely) pathogenic, and 1 uncertain. These duplications were often complex, involving coduplications or codeletions with other regions. CONCLUSION: Our findings challenge the presumption that intragenic DMD duplications are predominantly in tandem. This highlights the need for a cautious variant interpretation approach, particularly in carrier screening and other settings in which variants are identified without indications of dystrophinopathy.

Humans↗
PubMed2026

Nanoplate Digital PCR for Identification of α0-Thalassemia (SEA Deletion): Carrier Screening and Possible Application to Prenatal Diagnosis.

The Southeast Asian deletion (--SEA), the most prevalent &#x3b1;0-thalassemia mutation in Southeast Asia, is a major target of regional thalassemia prevention programs. Coinheritance of &#x3b1;0-thalassemia with other hemoglobinopathies, particularly hemoglobin E (Hb E), complicates routine hematological screening and requires reliable molecular confirmation. This study developed and validated a duplex nanoplate digital polymerase chain reaction (dPCR) assay for simultaneous identification of the wild-type &#x3b1;-globin and --SEA deletion alleles in a single reaction. The assay was established on the QIAcuity nanoplate platform and evaluated using 171 blinded leftover DNA specimens from individuals with Hb E. Diagnostic performance was compared with conventional gap-PCR. Distinct fluorescence amplitude patterns enabled discrimination among normal, heterozygous, and homozygous --SEA genotypes in a single closed tube. Among the 171 specimens, 70 were identified as --SEA carriers and 101 as non-carriers, showing 100% concordance with gap-PCR. All subjects with Hb E + A2 levels &#x2265; 25% were negative for the --SEA deletion, whereas 56.0% of those with levels < 25% carried the deletion. In the representative prenatal case, duplex dPCR accurately identified parental carrier status and a homozygous --SEA fetus. This assay provides an accurate and practical molecular confirmatory assay for thalassemia screening and prenatal diagnosis in Southeast Asia.

Humans↗
PubMed2026

Alpha-thalassaemia early eluting peak for alpha-thalassaemia --SEA carrier screening: a multicentre diagnostic comparison with immunochromatographic strip test and haemoglobin H inclusion test.

While high-performance liquid chromatography (HPLC) is well-established for &#x3b2;-thalassaemia and haemoglobinopathies, phenotypic screening for &#x3b1;0-thalassaemia has been limited. To address this limitation, we aimed to translate the discovery of the &#x3b1;-thalassemia early eluting peak (&#x3b1;EEP) in HPLC into clinical practice by comparing its diagnostic performance with other existing methods (haemoglobin H inclusion test [HbHi] and immunochromatographic strip test [ICT]) in a multicentre setting, and elucidating the nature of the &#x3b1;EEP by liquid chromatography-tandem mass spectrometry (LC-MS/MS). With a cohort of 820 genotyped patients, the &#x3b1;EEP showed superior diagnostic performance in detecting --SEA (sensitivity 99.6%, specificity 100%) compared with HbHi (sensitivity 95.8%, P&#x2009;=&#x2009;0.006; specificity 97.3%, P&#x2009;<&#x2009;0.001) and ICT (sensitivity 95.8%, P&#x2009;=&#x2009;0.006; specificity 75.4%, P&#x2009;<&#x2009;0.001). Both HbHi and ICT showed reduced sensitivity in &#x3b2;-thalassaemia carriers versus non-carriers. ICT showed reduced specificity when Hb F&#x2009;&#x2265;&#x2009;1% compared with <&#x2009;1%. The &#x3b1;EEP remained robust across all subgroups. LC-MS/MS revealed a strong association between the &#x3b1;EEP and embryonic &#x3b6;-globin chains (P&#x2009;<&#x2009;0.001). The &#x3b1;EEP offered cost reductions of 98.6% over HbHi and 97.3% over ICT. Collectively, the &#x3b1;EEP is a highly reliable and cost-effective marker for detecting --SEA carriers, enabling a novel "all-in-one" HPLC screening strategy for --SEA, &#x3b2;-thalassaemia and haemoglobinopathies. Trial registration number: not applicable.

Humans↗
PubMed1978

Role of the physician in screening for carriers of Tay-Sachs disease.

A screening test for carriers of Tay-Sachs disease has been available in Toronto for more than 6 years. In that time more than 11 000 Jewish residents have been tested. Most had requested testing after hearing about the screening program from friends or the media; few had been advised by their physicians to be tested. To sample the attitudes of physicians in Toronto towards carrier screening, we studied questionnaire responses of 42 physicians whose practices were composed largely of Jewish patients. Only 31% regularly advised their young adult Jewish patients to have a carrier screening test but 76% said they had patients who asked if they should be tested. Of the 14 (33%) who had had one or more patients with Tay-Sachs disease 6 did not advise carrier testing. There was a positive correlation between specialty training and support for the screening program. Methods for increasing physician advocacy of these programs are discussed.

Abortion, Induced↗
PubMed2024

Estimation of carrier frequencies of autosomal and X-linked recessive genetic conditions based on gnomAD v4.0 data in different ancestries.

PURPOSE: Monogenic rare diseases contribute significantly to infant deaths and pediatric hospitalizations and cause burden to the patients and their families. The American College of Medical Genetics and Genomics recommended in 2021 that carrier screening of autosomal recessive and X-linked conditions with a carrier frequency of &#x2265;1/200 and a severe or moderate phenotype should be offered when planning or during pregnancy. In November 2023 gnomAD v4.0 was released. It contains in total 807,162 individuals, being nearly 5&#xd7; larger than previous versions, which have been used to estimate gene carrier frequencies (GCF). METHODS: We utilized gnomAD v4.0 (GRCh38) to calculate the GCFs for available genetic ancestry groups for variants having pathogenic or likely pathogenic classification (>80% of submissions) in ClinVar. We calculated GCF separately for exomes and genomes, combined data, and at-risk couple frequencies (ACF) per genetic ancestry group. RESULTS: In total, 324 genes had a GCF &#x2265;1/200 in at least 1 ancestry subgroup. The number of genes with GCF &#x2265;1/200 varied greatly between subgroups. ACFs were more similar, Ashkenazi Jewish having the highest ACF of 6.11%. CONCLUSION: Improved understanding of carrier risks and updated carrier screening content would allow patients to make more informed reproductive decisions.

Humans↗
PubMed2024

Offering complex genomic screening in acute pediatric settings: Family decision-making and outcomes.

PURPOSE: Families of children in pediatric acute care who are offered ultrarapid genomic sequencing are making complex decisions during a high-stress period. To reduce complexity for families and clinicians, we offered genomic screening for the child and parents after the completion of diagnostic testing. We evaluated uptake, understanding, and service delivery preferences. METHODS: A cohort of 235 families who had completed ultrarapid diagnostic genomic sequencing at 17 Australian hospitals were offered up to 3 screens on their genomic data: pediatric-onset, adult-onset, and expanded couple carrier screening. We investigated decision making, understanding, and service delivery preferences using surveys at 3 time points (pre counseling, post counseling, and post result) and performed inductive content analysis of pretest genetic counseling transcripts. RESULTS: A total of 119 families (51%) attended genetic counseling with 115 (49%) accepting genomic screening. Survey respondents were more likely to find decisions about couple carrier screening easy (87%) compared with adult (68%; P&#xa0;= .002) or pediatric (71%; P&#xa0;= .01) screening decisions. All respondents with newly detected pathogenic variants accurately recalled this 1 month later. A delayed offer of screening was acceptable to most respondents (78%). CONCLUSION: Separating genomic screening from the stressful diagnostic period is supported by families who demonstrate good knowledge and recall. Our results suggest delaying genomic screening should be trialed more widely.

Humans↗
PubMed1976

[Comparative study of technics of screening of carriers of HBs antigen].

The purpose of this study was to compare the results of 3 reverse passive haemagglutination techniques currently used by blood centers for the HBS antigen screening in donors' blood. A comparison was also made with 3 other techniques: Radio-immuno-assay (RIA), Counter-electrophoresis (CEP), Complement fixation (CF). The sera from 2.028 blood donors were screened by all those techniques, as well as 105 known sera, used as references (87 HBS antigen positive sera with different titers, 18 HBS antigen negative sera) and coming from 4 origins: NIH-Bethesda, Centre National de Transfusion Sanguine, Paris; Hôpital de la Pitié-Salpêtrière, Paris; Hôpital Broussais, Paris. The reverse passive haemagglutination techniques were shown to be slightly less sensitive than RIA and definitely more sensitive than CEP and CF, since 18 sera were HBS antigen positive with RIA (0.88%), 10 or 12 with haemagglutination (0.40-0.59%), 8 with CF (0.39%) and 7 with CEP (0.34%). The frequency of false positive results changed with the haemagglutination technique used (0.84% for WH.HBS, to 2.3% for Hepanosticon) and involved confirmatory tests (absorption and/or neutralisation). In sum, the sensitivity, specificity and practicability of the 3 haemagglutination techniques were shown to be nearly identical, with a slight but sure advantage for the WH.HBS in our experiment. Thus reverse passive haemagglutination techniques seem, at the present time, to be the best ones for HBS antigen screening when RIA cannot be applied.

Carrier State↗