Carrier Screening Research Articles

Thalassemia genetic screening of pregnant women with anemia in Northern China through comprehensive analysis of thalassemia alleles (CATSA).

Thalassemia is an inherited blood disorder and traditionally considered more prevalent in Southern China. However, with increased migration and intermarriage, more and more thalassemia carriers had been reported in Northern China. The lack of screening for thalassemia carriers may also result in missed diagnosis in Northern China. Additionally, thalassemia carriers are usually asymptomatic or mild anemia, but their anemia can get worse during pregnancy. Iron deficiency anemia (IDA) is also one of the causes of anemia during pregnancy. In particular, both IDA and thalassemia are characterized by microcytic hypochromic anemia. The overlap of symptoms and the presence of thalassemia carriers with IDA may lead to misdiagnosis. In this study, long-read sequencing based approach termed comprehensive analysis of thalassemia alleles (CATSA) had been performed for 244 pregnant women in Northern China whose results of routine blood examinations were abnormal. As a result, 16.39 % (40/244) of the anemic pregnant women carried at least one mutation of thalassemia. One Hb H patient and a rare α-globin gene triplication combined with β-thalassemia were also identified. Of the 44 thalassemia variants detected, the -α3.7, -SEA and HBB:c.316-197C > T were the most common variants. CATSA is of great significance for determining exact genotype of 22.50 % (9/40) thalassemia carriers because 8 variants they carried were outside the detection range of routine genetic tests. It is noted that 2 novel deletions of HBA gene were identified, expanding the genotype spectrum of α-thalassemia. Our findings demonstrate the importance of thalassemia screening in Northern China. Future research should focus on expanding screening to include more diverse populations.

A next-generation sequencing-based universal target panel and algorithm for one-stop detection of copy number alterations and single-nucleotide variations in the HBB gene cluster for rapid diagnosis of β-thalassemia.

This study aimed to develop and validate a targeted next-generation sequencing (NGS) panel along with a data analysis algorithm capable of detecting single-nucleotide variants (SNVs) and copy number variations (CNVs) within the beta-globin gene cluster. The aim was to reduce the turnaround time in conventional genotyping methods and provide a rapid and comprehensive solution for prenatal diagnosis, carrier screening, and genotyping of β-thalassemia patients. We devised a targeted NGS panel spanning an 80.4 kb region on chromosome 11, encompassing the beta-globin gene cluster and 5' locus control region. We also developed an advanced data analysis algorithm consisting of variant calling and depth plot analysis that facilitates simultaneous detection of SNVs and CNVs in a single run. The test panel and algorithm were validated with 14 in-house β-thalassemia carrier/patient samples and cross-checked against the HbVar database. We identified seven pathogenic SNVs and five CNVs within the beta-globin gene cluster in various combinations, such as heterozygous, homozygous, and compound heterozygous conditions. Additionally, the coordinates of 169 rare deletions and 11 fusion mutations reported in the HbVar database were checked to verify the theoretical ability of our developed gene panel to detect all the CNVs within the target region. The developed panel and NGS technology can detect both SNVs and CNVs in a single run and can also be utilized for prenatal diagnosis and carrier screening for hemoglobinopathies, underscoring its versatility and clinical utility.

Thalassemia carrier screening among the college going students of the rural areas of West Midnapore, India

Thalassemia carrier screening among the college going students of the rural areas of West Midnapore, India

The effect of media aids in genetic carrier screening education among infertility patients

The effect of media aids in genetic carrier screening education among infertility patients

Preconception carrier screening in couples seeking in vitro fertilization: exploring the patient perspective

Research questionWhat is the level of understanding, and what are the attitudes and considerations regarding preconception carrier screening (PCS) among patients seeking in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI)? DesignA mixed methods design was used. Nine interviews were conducted with couples or individual partners (N = 16) who had an intake for IVF/ICSI in the two years prior to this study. A questionnaire was completed by 115 participants. No actual PCS was offered. ResultsAll interviewed couples expressed a positive attitude towards PCS, and over half of the respondents would pursue or seriously consider pursuing PCS if possible. Some couples falsely believed that PCS could identify a cause for their fertility problems and increase their chances of conceiving. The desire to make an informed reproductive decision was the most important argument in favour of PCS. The primary argument against PCS was the apprehension of being confronted with reproductive dilemmas. The longer the delay in their IVF/ICSI treatment required to perform PCS, the more couples would be inclined to decline screening. Participants preferred receiving information about PCS from a medical specialist at an early stage in their IVF/ICSI treatment. ConclusionAlthough attitudes towards PCS were generally positive, some concerns were raised about treatment delays and potential reproductive dilemmas, and some couples had misconceptions about the purpose of screening within the context of their IVF/ICSI treatment. These findings highlight the importance of tailoring the information and counseling to the specific needs of IVF/ICSI patients.

Unravelling variants in Farber disease: diagnostic and prenatal challenges in atypical presentations

Abstract Farber disease (FD; OMIM #228000), also known as Farber's lipogranulomatosis, is a rare lysosomal storage disease caused by acid ceramidase deficiency. Clinically, FD is typically identified by a triad of symptoms: subcutaneous nodules, joint pain, and voice hoarseness. However, diagnosing mild or attenuated variants can be difficult, as some symptoms may be absent or overlooked. In such cases, genetic testing is essential for confirming the diagnosis and enabling prenatal diagnosis. Case presentation A couple presented with a history of losing two children at 1.5 years of age, both of whom exhibited severe developmental delay, hypotonia, weak cry, and progressive skin lesions. Neither child underwent genetic testing, and no DNA samples were preserved. Subsequent parental carrier screening identified a heterozygous variant of uncertain significance (VUS) in the ASAH1 (N-Acylsphingosine Amidohydrolase 1) (OMIM #613468) gene in both parents. Exome sequencing was later performed on the couple’s third affected child, revealing compound heterozygous variants in the ASAH1 gene, consistent with those found in the parents. This case presented with atypical manifestations of FD, necessitating comprehensive investigations, including laboratory tests, radiological assessments, genetic analysis, and histopathological examination of skin biopsy samples. These findings led to the identification of likely pathogenic mutations in ASAH1. Based on these results, prenatal diagnosis was successfully conducted in the couple's fourth pregnancy. Conclusion This case illustrates the challenges of diagnosing FD when atypical presentations and genetic variants of uncertain significance are involved. The absence of classic symptoms like subcutaneous nodules and the presence of an ASAH1 gene variant complicated the diagnosis and delayed options for prenatal diagnosis in future pregnancies. It underscores the critical role of genetic testing and the need to reclassify VUS through detailed genotype–phenotype correlations to enhance diagnostic accuracy and support timely interventions.

Nationwide survey on awareness of consanguinity and genetic diseases in Saudi Arabia: challenges and potential solutions to reduce the national healthcare burden

BackgroundConsanguineous marriage is a major contributing factor for many genetic diseases and a burden to the healthcare system and national economy due to costly long-term care. Earlier studies highlighted the significantly limited awareness of the higher prevalence of genetic disease due to consanguinity even among the educated Arabs. In Saudi Arabia, more than 50% of marriages are between first cousins. This national study aims to gauge the level of the public awareness regarding the consanguinity and its impact on prevalence of genetic diseases across the Saudi Arabia.MethodsA cross-sectional bilingual online survey was conducted across Saudi Arabia, distributed through a variety of social media platforms for all residents. Pooled summary data was used from the participants.ResultsMajority of the 9191 participants are < 30 years of age (72.85%), single (61.35%), women (74.12%) and college educated (77.16%). Consanguineous marriages are common in the extended family of 61.24% of participants. Though majority of them (85.45%) recognise the higher genetic disease risk associated with consanguinity, low awareness among men was observed (76.61 vs 88.53%). Sickle cell anaemia and thalassemia were not considered as genetic diseases by 60.68% of males and 48.39% of females, though they are the most common genetic diseases in Saudi Arabia. More women are aware of the carrier screening tests than men (42.62 vs 34.56%). Only 6.87% know the rationale behind the national mandatory premarital screening tests and the diseases screened. Although almost all (99.18%) are active users of the social media, 47.77% of men and 57.17% of women use them to search for health-related information.ConclusionThe present study, one of the largest national surveys in highly consanguineous society, highlights that even the young and college-educated participants have low awareness of the genetic disease burden, which is strikingly high in all corners of the country. Social media platforms can be used by genetic professionals and national organizations to disseminate the reliable educational material to the public to reduce the national healthcare and economic burden in the future.

Autosomal Recessive Non-Syndromic Hearing Loss: A Case Report with a Novel TRIOBP Gene Variant

In the present case report, we have found a novel variant for TRIOBP in a patient with congenital hearing loss. The patient is an 8-year-old female with hearing loss, the first child of consanguineous parents. To identify the underlying genetic defect, whole genome sequencing was performed. Carrier screening of the parents was also conducted. The results showed a homozygous autosomal recessive missense c.5849C&gt;T (p.Pro1950Leu) variant in exon 16 of the TRIOBP gene. To our knowledge, this variant has not been previously reported as either a pathogenic or a benign variant. The novel TRIOBP variant found in the present study broadens the range of TRIOBP mutations implicated in hearing loss. Accordingly, the results of this study may be important for genetic counseling.

Perceptions of severity and their influence on reproductive decision-making following reproductive genetic carrier screening.

The concept of severity in healthcare is multidimensional and subjective. It is a primary consideration in reproductive genetic carrier screening design where the focus is providing reproductive couples with information about the chance of severe genetic conditions in their offspring. When offering this screening, it is important to understand how condition severity is perceived and incorporated into reproductive decision-making. We analysed data from 41 semi-structured interviews with people who received a screening result indicating an increased chance for having children with a genetic condition. Thematic analysis revealed a desire for comprehensive information about the condition including clinical features, prognosis, impact on quality of life and treatment/management options. Participants integrated this information with their personal circumstances, beliefs/values and lived experience to form a perception of the severity of the condition. For rare and reduced-penetrance conditions where clinical information was limited or ambiguous, decision-making was more complex and greater anxiety was experienced. For conditions with a severity spectrum, reproductive decisions were based on the 'worst-case' clinical presentation. Where the impact of the condition was perceived as significant, the imperative to avoid that condition in future children appeared to be the greatest. Participants reported feeling that knowing their increased reproductive chance of the condition conferred a responsibility to avoid the condition, to prevent suffering and/or reduced quality of life for their children and future generations. These findings offer critical insight into how severity is perceived and the role it plays in reproductive decision-making and justifies a carefully considered approach to screening panel design.

Comprehensive copy number analysis of spinal muscular atrophy among the Iranian population

Copy number variations in the SMN1 gene on chromosome 5 are the primary cause of Spinal Muscular Atrophy (SMA) disease, characterized by muscle weakness and degeneration due to impaired alpha motor neurons in the spinal cord. To obtain a comprehensive molecular understanding of the SMA, including carriers, silent carriers, and patients in the Iranian population, we analyzed data from 5224 individuals referred to Kariminejad - Najmabadi Pathology & Genetics Center, Tehran, Iran, between 2006 and 2023 using MLPA and quantitative RT-PCR methods. The carrier frequency of SMA was estimated to be 5.55%. Furthermore, 3.06% of SMA parents (n = 24) had two copies of the SMN1 gene. Among 725 patients, those with an earlier onset of SMA were more likely to have two copies of the SMN2 gene (46.45%) and no copies of the NAIP gene (49.36%). Among the 654 fetal samples screened for SMA, 22.33% were found to be affected, while 3.46% of their parents tested normal. These findings are valuable for genetic counseling, carrier screening, and prenatal diagnosis of SMA in Iran. Furthermore, they underscore the importance of CNV analysis of SMN1, SMN2, and NAIP genes for accurate diagnosis and prognosis of SMA.

Population-based genetic carrier screening. A consensus statement from the Spanish societies: AEGH, AEDP, ASEBIR, SEAGEN, SEF and SEGCD.

Autosomal recessive or X-linked disorders are passed from parents to offspring through Mendelian inheritance patterns and may lead to severe clinical manifestations in early childhood development. Together, the Spanish Association of Human Genetics (AEGH), Association for the Study of Reproductive Biology (ASEBIR), Spanish Association of Genetic Counselling (SEAGEN), Spanish Fertility Society (SEF), Spanish Society of Clinical Genetics and Dysmorphology (SEGCD), and the Spanish Association of Prenatal Diagnostics (AEDP) developed a consensus statement for population-based genetic carrier screening (GCS). The presented opinion statement recommends that preconception GCS services be included in the public healthcare system to support couples' reproductive autonomy and timely medical decision-making. Program design and implementation strategies, as well as key technical, ethical, and legal considerations are discussed.

Preconception carrier screening among assisted reproduction patients: insights from a monocentric survey in France

Preconception carrier screening among assisted reproduction patients: insights from a monocentric survey in France

Mitigating adverse pregnancy and neonatal outcomes through expanded carrier screening in an oocyte donation programme

Research questionHow frequent are adverse outcomes (AO) in an oocyte donation (OD) program and how many recessive conditions can be prevented with the implementation of expanded carrier screening (ECS)? DesignRetrospective observational study using data from OD cycles between January 2014 and December 2021 in the Reproductive Medicine Unit of a University Hospital in Spain.AO were studied in 4565 OD cycles and the number of high-risk assignations was identified in the OD program where ECS was applied to the oocyte donors and the recipient's male partner (or sperm donor, in cases of double donation). ResultsOut of 4565 OD cycles, 67 OD recipients (1.47%) reported an adverse obstetrical or neonatal outcome. Genetic aetiology was confirmed in 25 (37.3%) cases. The remaining 42 (62.7%) cases involved congenital malformations, neurodevelopmental disorders, and other conditions with unknown genetic origins.Moreover, 211 (4.6%,211/4565) high-risk assignations were identified due to both oocyte donors and recipient's male partners being carriers of the same autosomal recessive (AR) condition. This could have led to an additional 1,15% of children born with an AR condition (25%x4.6%). Additionally, 52 (2.8%,52/1875) oocyte donor candidates were carriers of X-linked (XL) conditions, which would have led to an additional 0.7% (25%x2.8%) of children born with an XL disorder.ECS implementation resulted in a 55.7% reduction in AO risk, decreasing the potential AO rate from a 3.32% rate (1.15%+0.7%+1.47%) to an actual incidence of 1.47%. ConclusionsECS reduces the probability that children born from OD could inherit recessive conditions screened. However, certain adverse outcomes remain unavoidable.

Considering severity in the design of reproductive genetic carrier screening programs: screening for severe conditions.

Reproductive genetic carrier screening (RGCS) provides information about people's chance of having children with certain genetic conditions, to inform reproductive decision making. RGCS at population scale requires a robust and streamlined program that is purposively designed and formally implemented to ensure equity and consistency. There are many considerations in selecting conditions, genes and variants for inclusion in RGCS, with severity of the genetic condition a key criterion. However, the concept of severity is complex and often underspecified in available guidelines. Severity is often determined in relation to other contextual features and can be experienced differently by individuals who all have the same condition. While some genetic conditions are unambiguously considered severe, there are many factors that contribute to how severe a condition is perceived to be (and by whom), and perspectives will vary. In this paper, we analyse why severity is an important criterion when selecting conditions, genes or variants to be included in RGCS. We suggest that screening programs should be oriented more towards variants and genes associated with severe conditions. We discuss the importance of taking a practical approach to gene selection in a carrier screening program when presenting the offer at population scale.

Nationwide, Couple-Based Genetic Carrier Screening

BackgroundGenomic sequencing technology allows for identification of reproductive couples with an increased chance, as compared with that in the general population, of having a child with an autosomal recessive or X-linked genetic condition.MethodsWe investigated the feasibility, acceptability, and outcomes of a nationwide, couple-based genetic carrier screening program in Australia as part of the Mackenzie’s Mission project. Health care providers offered screening to persons before pregnancy or early in pregnancy. The results obtained from testing at least 1281 genes were provided to the reproductive couples. We aimed to ascertain the psychosocial effects on participants, the acceptability of screening to all participants, and the reproductive choices of persons identified as having an increased chance of having a child with a condition for which we screened.ResultsAmong 10,038 reproductive couples enrolled in the study, 9107 (90.7%) completed screening, and 175 (1.9%) were newly identified as having an increased chance of having a child with a genetic condition for which we screened. These conditions involved pathogenic variants in 90 different genes; 74.3% of the conditions were autosomal recessive. Three months after receiving the results, 76.6% of the couples with a newly identified increased chance had used or planned to use reproductive interventions to avoid having an affected child. Those newly identified as having an increased chance had greater anxiety than those with a low chance. The median level of decisional regret was low in all result groups, and 98.9% of participants perceived screening to be acceptable.ConclusionsCouple-based reproductive genetic carrier screening was largely acceptable to participants and was used to inform reproductive decision making. The delivery of screening to a diverse and geographically dispersed population was feasible. (Funded by the Medical Research Future Fund of the Australian government; ClinicalTrials.gov number, NCT04157595.)

Expanded carrier screening for 224 monogenic disease genes in 1,499 Chinese couples: asingle-center study.

Expanded carrier screening (ECS) is a preventive genetic test that enables couples to know their risk of having a child affected by certain monogenetic diseases. This study aimed to evaluate the carrier frequency for rare monogenic diseases in the general Chinese population and the impacts of ECS on their reproductive decisions and pregnancy outcomes. This single-center study was conducted between September 2022 and April 2023. An ECS panel containing 224 recessive genes was offered to 1,499 Chinese couples from the general population who were at early gestational ages or planned to conceive. Overall, 55.0 % of the individuals carried for at least one recessive condition. There were 16 autosomal recessive (AR) genes with a carrier frequency of≥1/100 and 22 AR genes with a carrier frequency of <1/100 to ≥1/200. The most common AR and X-linked diseases were GJB2-related non-syndromic hearing loss, and hemolytic anemia, respectively. Fifty-five couples (3.67 %; 1 in 27.3) were at increased risk of having an affected child with 19 pregnant at the time of testing. Of these, 10 opted for amniocentesis, and four affected pregnancies were identified, with three of them being terminated. This study not only provides valuable information about the recessive genetic landscape, but also establishes a solid foundation for couple-based ECS in a real clinical setting.

Leveraging diverse genomic data to guide equitable carrier screening: Insights from gnomAD v.4.1.0.

Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.0) revealed a significant carrier burden of pathogenic/likely pathogenic (P/LP) variants in genes associated with autosomal-recessive conditions across diverse ancestral populations. Carrier screening panels are routinely offered to reproductive partners to inform their risk of having an affected child. Current guidelines from the American College of Medical Genetics and Genomics (ACMG) recommend screening for genes with a carrier frequency of at least 1/200 and associated with moderate/severe conditions. Here, we systematically analyzed >700,000 gnomAD v.4.1.0 exomes spanning eight ancestries to estimate the carrier frequency of P/LP variants in 2,987 genes associated with autosomal-recessive conditions. After expert curation for clinical severity, we identified 286 genes meeting the criteria for carrier screening. The number of genes exceeding the 1/200 threshold varied across populations, with 40 in the South Asian ancestry and up to 119 in the Ashkenazi Jewish population. Simulations showed that pan-ethnic screening panels offer advantages for individuals of diverse or admixed ancestry, while ancestry-specific panels may be preferable for genetically homogeneous populations. This study leveraged the most comprehensive genomic dataset to date to provide an updated candidate gene list for equitable carrier screening across diverse populations. Our findings highlight the need for continued expansion of genomic resources to better understand rare disease risk and inform screening efforts in underrepresented groups.

Rapid screening and experimental investigation of oxygen carriers for chemical looping oxidative dehydrogenation of ethane

Chemical looping oxidative dehydrogenation of ethane (CLODHE) is a promising alternative to ethylene production. The key to this technology is the development of oxygen carriers. In this paper, a novel rapid screening strategy for perovskite oxygen carriers, based on machine learning and thermodynamics, is proposed. Dozens of thermodynamically feasible oxygen carriers were screened for the CLODHE process and three of them were selected for further experimental verification. Among the selected oxygen carriers, LaCuO3 had the best performance. LaCuO3 achieved an ethane conversion of 51.3 % and an ethylene selectivity of 93.93 % over 10 cycles at 750 °C and 18,000 ml·h-1·g-1, respectively. XPS patterns showed that the composition and content of oxygen remained almost unaltered before and after the cycling, which may be the reason for its stability. The decreased in Cu3+ indicated it played a crucial role in oxidative dehydrogenation of ethane. SEM-EDS patterns showed that the oxygen carriers became agglomerated after cycling, leading to a slight reduction in reactivity. The proposed strategy is appropriate for binary to quaternary perovskites and can also be applied to other reactions, providing insights into material design and accelerating their development.

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

PurposeFamilies 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. MethodsA 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. ResultsA 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 = .002) or pediatric (71%; P = .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%). ConclusionSeparating 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.

Management of Prenatal Expanded Genetic Carrier Screening Results for Autosomal Recessive Sensorineural Hearing Loss.

Expanded carrier screening (ECS) identified couples at-risk to have a baby with an autosomal recessive genetic condition. Several genes implicated in sensorineural hearing loss (SNHL) are included in prenatal or preconception genetics ECS testing. Early identification of SNHL risk may enable prognostication of hearing loss, early educational intervention, and minimization of unnecessary diagnostic testing. We sought to describe cases where ECS enabled early SNHL-risk identification. Retrospective chart review. Maternal-Fetal Care Center and Otolaryngology department at an academic tertiary hospital. Medical records of parent-infant dyads with positive ECS results for variants in autosomal recessive SNHL genes were reviewed. Data regarding genetic diagnostic testing, newborn hearing screening, time to HL diagnosis, audiological evaluation, and clinical consultations were compiled. Fifteen pregnant with positive ECS results for SNHL were referred for consultation with a pediatric otolaryngologist and genetic counselor. Generally, these couples were highly educated and adequately insured. 14 had pathogenic variants for GJB2 and 1 for USH2A. Four couples pursued prenatal genetic diagnosis via amniocentesis; 11 couples deferred genetic testing to the postnatal period or waited for initial hearing evaluation. Six babies inherited biallelic GJB2 mutations. Four were found to have SNHL on ABR by age 5 weeks and received follow-up management, 1 had a normal hearing evaluation despite being gene-positive, and 1 was lost to follow-up before hearing evaluation. Carrier screening and confirmatory prenatal or neonatal genetic testing provided considerable lead time for early audiometric testing and appropriate intervention services including hearing aid fitting.