Genetic Screening Tests Research Articles

Exonic Short Interspersed Nuclear Element Insertion in FAM161A Is Associated with Autosomal Recessive Progressive Retinal Atrophy in the English Shepherd.

Progressive retinal atrophies (PRAs) are a genetically heterogeneous group of inherited eye diseases that affect over 100 breeds of dog. The initial clinical sign is visual impairment in scotopic conditions, as a consequence of rod photoreceptor cell degeneration. Photopic vision degeneration then follows, due to progression of the disease to the cone photoreceptors, and ultimately results in complete blindness. Two full-sibling English Shepherds were diagnosed with PRA at approximately 5 years old and tested clear of all published PRA genetic variants. This study sought to identify the novel PRA-associated variant segregating in the breed. We utilised a combined approach of whole genome sequencing of the probands and homozygosity mapping of four cases and 22 controls and identified a short interspersed nuclear element within an alternatively spliced exon in FAM161A. The XP_005626197.1 c.17929_ins210 variant was homozygous in six PRA cases and heterozygous or absent in control dogs, consistent with a recessive mode of inheritance. The insertion is predicted to extend exon 4 by 39 aberrant amino acids followed by an early termination stop codon. PRA is intractable to treatment, so the development of a genetic screening test, based on the associated variant, is significant, because it provides dog breeders/owners with a means of reducing the frequency of the disease variant within this breed as well as minimising the risk of breeding puppies that will develop this blinding disease.

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.

Neuroleptic malignant syndrome and serotonin syndrome: a comparative bibliometric analysis

ObjectiveThis study aimed to analyze and map scientific literature on Neuroleptic Malignant Syndrome (NMS) and Serotonin Syndrome (SS) from prestigious, internationally indexed journals. The objective was to identify key topics, impactful articles, prominent journals, research output, growth patterns, hotspots, and leading countries in the field, providing valuable insights for scholars, medical students, and international funding agencies.MethodsA systematic search strategy was implemented in the PubMed MeSH database using specific keywords for NMS and SS. The search was conducted in the Scopus database, renowned for its extensive coverage of scholarly publications. Inclusion criteria comprised articles published from 1950 to December 31st, 2022, restricted to journal research and review articles written in English. Data were analyzed using Microsoft Excel for descriptive analysis, and VOSviewer was employed for bibliometric mapping.ResultsThe search yielded 1150 articles on NMS and 587 on SS, with the majority being case reports. Growth patterns revealed a surge in NMS research between 1981 and 1991, while SS research increased notably between 1993 and 1997. Active countries and journals differed between NMS and SS, with psychiatry journals predominating for NMS and pharmacology/toxicology journals for SS. Authorship analysis indicated higher multi-authored articles for NMS. Top impactful articles focused on review articles and pathogenic mechanisms. Research hotspots included antipsychotics and catatonia for NMS, while SS highlighted drug interactions and specific medications like linezolid and tramadol.ConclusionsNMS and SS represent rare but life-threatening conditions, requiring detailed clinical and scientific understanding. Differential diagnosis and management necessitate caution in prescribing medications affecting central serotonin or dopamine systems, with awareness of potential drug interactions. International diagnostic tools and genetic screening tests may aid in safe diagnosis and prevention. Reporting rare cases and utilizing bibliometric analysis enhance knowledge dissemination and research exploration in the field of rare drug-induced medical conditions.

Current status and future of genomics in fetal and maternal medicine: A scientific review commissioned by European Board and College of Obstetrics and Gynaecology (EBCOG)

This EBCOG guidance reviews the current and future status of genomics within fetal and maternal medicine. This document addresses the clinical uses of genetic testing in both screening and diagnostic testing prenatally. The role of genomics within fetal and maternal medicine is described. The research and future implications of genetic testing as well as the educational, ethical and economic implications of genomics are discussed.

Abstract PO2-20-06: Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience

Abstract Background Cancer therapy related cardiac dysfunction (CTRCD) is a significant side effect of several chemotherapies, targeted agents, and immunotherapies integral to treatment. Anthracyclines are an example of a commonly used chemotherapy drug class that can cause irreversible early and late onset heart failure. CTRCD often leads to dose reductions and treatment delays or cessation, limiting treatment success and contributing to increased mortality and life-long morbidity in oncology survivors. In Australia, there are currently no multi-centre, longitudinal studies examining CTRCD in adult oncology patients. Trial design The Australian Cardiology-Oncology Registry (ACOR) is a prospective observational non-interventional study involving 14 sites across Australia. Patient information is obtained from hospital medical records and de-identified upon entry into the registry. Patient demographics, medical history, cancer diagnosis, treatment, cardiac evaluations, and the management of demonstrated CTRCD are recorded. Data is collected at baseline (prior to treatment), and then at six-monthly intervals thereafter. Additionally, patients who develop anthracycline-induced cardiotoxicity (ACT) will be asked to participate in the biobanking study, which will involve a one-off 12mL peripheral blood draw that will be processed at an external site for whole genome exome sequencing and the development of pluripotent derived stem cell cardiomyocytes. Eligibility criteria Inclusion Criteria • Adult oncology patients (>18+ years of age) treated with cardiotoxic therapies within the last 5-years Exclusion Criteria • Diagnosis of Trisomy 21 • Patients being treated with palliative intent Specific aims Chris O’Brien Lifehouse aims to use the ACOR to explore the epidemiology, clinical presentation, and management of CTRCD amongst adult oncology patients receiving cardiotoxic therapies. In addition, a biobanking sub-study will attempt to identify gene polymorphisms predisposing individuals to developing ACT. It is hoped that such longitudinal data collection can lead to the introduction of an ACT susceptibility genetic screening test allowing for the inclusion of patient risk stratification prior to anthracycline exposure in routine cancer treatment. Statistical methods Descriptive statistics will be used for variables for quantitative analysis. Kaplan Meier analyses will be used for survival curves, freedom from cardiac failure since enrolment and freedom from arrhythmia since enrolment. An annual report will be produced. Present accrual and target accrual At the time of submission, 224 adult oncology patients have been recruited to the ACOR via Chris O’Brien Lifehouse with the opening of the biobanking sub-study currently in progress. The ACOR anticipates with full registered site capacity to capture 600 patients annually. Citation Format: Jocelyn Finney, Ben Felmingham, Sanjeev Kumar, Alina Mahmood, Lisa Horvath, David Celermajer, Rachel Conyers. Using the Australian Cardio-Oncology Registry to study long-term cancer therapy related cardiac dysfunction in adult oncology patients – The Chris O’Brien Lifehouse experience [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-20-06.

Reducing decisional conflict in decisions about prenatal genetic testing: the impact of a dyadic intervention at the start of prenatal care.

Decisional conflict and regret about prenatal genetic screening and diagnostic tests may have important consequences in the current pregnancy and for future reproductive decisions. Identifying mechanisms that reduce conflict associated with the decision to use or decline these options is necessary for optimal patient counseling. We conducted a cluster-randomized controlled trial of a shared decision-making tool (NEST) at the beginning of prenatal care. Enrolled patients completed follow-up surveys at the time of testing (QTT) and in the second-third trimester (QFF), including the Decision Conflict Scale (DCS). Total DCS scores were analyzed using a multivariate linear mixed-effect model. Of the total number of participants (n=502) enrolled, 449 completed the QTT and QFF surveys. The mean age of participants was 31.6±3.8, with most parous at the time of study participation (n=321; 71.7 %). Both the NEST (the intervention) and control groups had lower median total DCS scores at QFF (NEST 13.3 [1.7, 25.0] vs. control 16.7 [1.7, 25.0]; p=0.24) compared to QTT (NEST 20.8 [5.0, 25.0] vs. control 18.3 [3.3, 26.7]; p=0.89). Participants exposed to NEST had lower decisional conflict at QFF compared to control (β-3.889; [CI-7.341,-0.437]; p=0.027). Using a shared decision-making tool at the start of prenatal care decreased decisional conflict regarding prenatal genetic testing. Such interventions have the potential to provide an important form of decision-making support for patients facing the unique type of complex and preference-based choices about the use of prenatal genetic tests.

Understanding the Awareness of Prenatal Genetic Screening Tests Among Pregnant Women in India: A Cross-Sectional Study.

Introduction Genetic disorders pose a significant health challenge in India, with chromosomal abnormalities ranking second only to congenital anomalies in terms of disease burden. Prenatal testing offers a crucial strategy for identifying and managing these disorders. However, the awareness and understanding of prenatal screening tests among pregnant women in India remain understudied. This study aims to fill this gap by investigating the awareness quotient of prenatal screening tests for genetic disorders among pregnant women in India. Methods A hospital-based cross-sectional study was conducted at the Genetics Unit, Department of Anatomy, and Department of Obstetrics and Gynecology, All India Institute of Medical Sciences, Mangalagiri. Ethical clearance was obtained, and data were collected using a self-administered questionnaire covering demographic characteristics and awareness assessment. Descriptive statistics, chi-square tests, and logistic regression analysis were employed for data analysis. Results Among the 200 pregnant women surveyed, the majority demonstrated inadequate awareness of prenatal screening tests for genetic disorders, with only 36.5% possessing adequate knowledge. Significant associations were found between awareness levels and factors such as age, trimester of pregnancy, and education level. Notably, awareness about non-invasive prenatal testing (NIPT) was notably low at 7%, indicating a need for targeted educational interventions. Comparison with international studies revealed varying levels of awareness across different populations, highlighting the influence of socio-cultural factors and healthcare systems. Conclusion This study underscores the need for improved awareness of prenatal screening tests among pregnant women in India. Addressing disparities in awareness, particularly among younger age groups and those with lower education levels, is crucial for informed decision-making in prenatal care. Targeted educational interventions can empower pregnant women to make informed choices, ultimately contributing to better maternal and child health outcomes. Further research should explore the effectiveness of such interventions in diverse settings to enhance prenatal care delivery.

Harnessing Next-Generation Sequencing as a Timely and Accurate Second-Tier Screening Test for Newborn Screening of Inborn Errors of Metabolism.

In this study, we evaluated the implementation of a second-tier genetic screening test using an amplicon-based next-generation sequencing (NGS) panel in our laboratory during the period of 1 September 2021 to 31 August 2022 for the newborn screening (NBS) of six conditions for inborn errors of metabolism: citrullinemia type II (MIM #605814), systemic primary carnitine deficiency (MIM #212140), glutaric acidemia type I (MIM #231670), beta-ketothiolase deficiency (#203750), holocarboxylase synthetase deficiency (MIM #253270) and 3-hydroxy-3-methylglutaryl-CoA lyase deficiency (MIM # 246450). The custom-designed NGS panel can detect sequence variants in the relevant genes and also specifically screen for the presence of the hotspot variant IVS16ins3kb of SLC25A13 by the copy number variant calling algorithm. Genetic second-tier tests were performed for 1.8% of a total of 22,883 NBS samples. The false positive rate for these six conditions after the NGS second-tier test was only 0.017%, and two cases of citrullinemia type II would have been missed as false negatives if only biochemical first-tier testing was performed. The confirmed true positive cases were citrullinemia type II (n = 2) and systemic primary carnitine deficiency (n = 1). The false positives were later confirmed to be carrier of citrullinemia type II (n = 2), carrier of glutaric acidemia type I (n = 1) and carrier of systemic primary carnitine deficiency (n = 1). There were no false negatives reported. The incorporation of a second-tier genetic screening test by NGS greatly enhanced our program's performance with 5-working days turn-around time maintained as before. In addition, early genetic information is available at the time of recall to facilitate better clinical management and genetic counseling.

Using exome analysis as a tool for genetics acquaintance in a psychiatry residence program

Objective: In this paper, a residency program at a Brazilian University Hospital shares its experience with a genetic screening test during the investigation of an inpatient with schizophrenia features. Method: A whole exome sequencing study investigation of a clozapine-refractory patient with schizophrenia served as a facilitator for mastering skills in genetics. Results: During the hospitalization of a 26-year-old patient with clozapine-refractory schizophrenia, the medical residency team noted syndromic features, such as retrognathia, large ear pinnae, pectus excavatum, and a longer wingspan relative to height. These findings led to an interest in genetic evaluation using exome sequencing. The exam showed variations in TMEM106B, IRF2BPL, and ALKBH8, leading to the hypothesis of polygenic heritage. The variations found are previously linked to a wide variety of neuropsychiatric syndromes. Conclusions: Clinical practice in modern psychiatry demands deep knowledge in genetics as genetic and pharmacogenetic tests become more accessible. Genetic training is imperative for the 21st-century psychiatric resident so that one can critically assess this field of knowledge. In this paper, a residency program at a Brazilian University Hospital shares its experience in genetics learning.

A cost-benefit analysis of genetic screening test for breast cancer in Iran

BackgroundThis study aimed to evaluate the implementation of the population- and family history (FH) -based screening for BReast CAncer (BRCA) in Iran, a country where less than 10% of breast cancer cases are attributable to a gene mutation.MethodsThis was an economic evaluation study. The Benefit-Cost Ratio (BCR) for genetic screening test strategies in Iranian women older than 30 was calculated. To this end, the monetary value of the test was estimated using the willingness-to-pay (WTP) approach using the contingent valuation method (CVM) by payment card. From a healthcare perspective, direct medical and non-medical costs were considered and a decision model for the strategies was developed to simulate the costs. A one-way sensitivity analysis assessed the robustness of the analysis. The data were analyzed using Excel 2010.Results660 women were included for estimating WTP and 2,176,919 women were considered in the costing model. The cost per genetic screening test for population- and FH-based strategies was $167 and $8, respectively. The monetary value of a genetic screening test was $20 and it was $27 for women with a family history or gene mutation in breast cancer. The BCR for population-based and FH-based screening strategies was 0.12 and 3.37, respectively. Sensitivity analyses confirmed the robustness of the results.ConclusionsThis study recommends the implementation of a FH-based strategy instead of a population-based genetic screening strategy in Iran, although a cascade genetic screening test strategy should be evaluated in future studies.

Complexity of the Genetic Background of Oncogenesis in Ovarian Cancer-Genetic Instability and Clinical Implications.

Ovarian cancer is a leading cause of death among women with gynecological cancers, and is often diagnosed at advanced stages, leading to poor outcomes. This review explores genetic aspects of high-grade serous, endometrioid, and clear-cell ovarian carcinomas, emphasizing personalized treatment approaches. Specific mutations such as TP53 in high-grade serous and BRAF/KRAS in low-grade serous carcinomas highlight the need for tailored therapies. Varying mutation prevalence across subtypes, including BRCA1/2, PTEN, PIK3CA, CTNNB1, and c-myc amplification, offers potential therapeutic targets. This review underscores TP53's pivotal role and advocates p53 immunohistochemical staining for mutational analysis. BRCA1/2 mutations' significance as genetic risk factors and their relevance in PARP inhibitor therapy are discussed, emphasizing the importance of genetic testing. This review also addresses the paradoxical better prognosis linked to KRAS and BRAF mutations in ovarian cancer. ARID1A, PIK3CA, and PTEN alterations in platinum resistance contribute to the genetic landscape. Therapeutic strategies, like restoring WT p53 function and exploring PI3K/AKT/mTOR inhibitors, are considered. The evolving understanding of genetic factors in ovarian carcinomas supports tailored therapeutic approaches based on individual tumor genetic profiles. Ongoing research shows promise for advancing personalized treatments and refining genetic testing in neoplastic diseases, including ovarian cancer. Clinical genetic screening tests can identify women at increased risk, guiding predictive cancer risk-reducing surgery.

Genetic Associations of Oral Clefts in Arabs.

This study aims to investigate genetic association between Non-syndromic Cleft lip with or without palate (NCLP) and 14 specific Single Nucleotide Polymorphism (SNPs) reported to be associated with NCLP from previous Genome Wide Association Studies (GWAS). A prospective case-control study. Ministry of Health (MOH) Cleft and Craniofacial Clinic and Kuwait University. One hundred sixty-four NCLP patients were recruited from MOH Cleft and Craniofacial clinic, and 491 controls from the Kuwait DNA bank established at Kuwait University. Total gDNA was extracted from whole blood withdrawn from patients and genotyped by real time PCR. Hardy-Weinberg Equilibrium was tested, and the set p value for significance (p < 0.05) was adjusted using the Benjamini - Hoochberg procedure to achieve 5% false discovery rate. Logistic regression multivariate analysis was used to test statistically significant differences between cases and controls. Genotyping both groups for the variants was determined through the allele discrimination software program. There was statistically significant difference between cases and controls in relation to two SNPs; LOC102724968 (rs13041247) (MAF cases/control = C (0.28/0.39) OR Homozygous = 1.30; 95% CI = 1.09-1.56, p = 0.0041) and PVT1 (rs987525) (MAF cases/control = A (0.41/0.27) OR heterozygous = 1.48; 95% CI =1.12-1.95, p = 0.0073), increasing the susceptibility to NCLP. Genetic variations are associated with the occurrence of oral clefts. Customized Next Generation Sequencing (NGS) panel to the Arab ethnicity is encouraged. In Addition, national preconception genetic carrier screening tests should expand to include common craniofacial anomalies.

New insights into the genetics of mandibular retrognathism: novel candidate genes.

Mandibular retrognathism (MR) is acommon skeletal malocclusion in humans with astrong genetic component. Single nucleotide polymorphisms (SNPs) in genes encoding epidermal growth factor (EGF) and EGF receptor (EGFR) could be involved in the etiology of mandibular retrognathism. Therefore, in this study, we investigated whether SNPs in the genes encoding for EGF and EGFR are associated with MR in German teenagers. This nested case-control study evaluated German orthodontic patients, aged 10-18years. DNA, which was isolated from buccal epithelial cells using two cytobrushes, was used for genotyping analysis and digital pretreatment lateral cephalograms were examined to calculate SNB and ANB. Patients with aretrognathic mandible (SNB < 78°) were included as cases, while patients with an orthognathic mandible (SNB = 78-82°) were included as controls. Four SNPs in the genes encoding for EGF and EGFR were chosen and genotyped using real-time PCR. Allele, genotype, and haplotype frequency were compared across groups (α = 5%). Finally, 119 patients were included in this study (45orthognathic mandible, 74retrognathic mandible). The minor alleleG in rs4444903 (EGF) was statistically more frequent in individuals with an orthognathic mandible (p = 0.008). The haplotype formed by the mutant alleles for rs4444903|rs2237051 (EGF; G|A) was statistically more frequent in the orthognathic mandible group (p = 0.007). The SNPs rs4444903 and rs2237051 in EGF, and rs2227983 in EGFR were statistically associated with adecreasing risk of developing aretrognathic mandible according to univariate and multivariate statistical analysis (p < 0.05). SNPs in EGF (rs4444903 and rs2237051) and EGFR (rs2227983) were associated with MR in our German sample and could be genetic biomarkers for early and individualized diagnostic identification of retrognathic mandibular development by means of genetic screening tests.

Determination of The GALT Gene in Galactosemic Cataract Patients in Azerbaijan

Galactosemia is one of the genetic diseases that can be treated thanks to early detection by genetic screening test. Galactosemia is a hereditary metabolic disease. This disease is heterogeneous and controlled by GALT, GALK, GALE and GALM genes. The presented article is dedicated to galactosemic disease among Azerbaijani patients as a result of GALT (galactose-1-phosphate uridyltransferase) gene mutations. This study reviews discusses the type of cataracts associated with galactosemia. The genetics of galactosemic patients are evaluated and details of galactose metabolism are described. This study describes the results of the GALT gene analysis of two Azerbaijanian patients with Galactosemic cataract. In one of the patients the heterzygous form of the same mutation, and the homozygous form in the other patient were found. In this study, control and experimental groups were determined, and DNA extracted from the peripheral blood of patients belonging to both groups was subjected to PCR amplification according to standard protocols and sequenced by Sanger sequence method. The symptoms of the disease were reviewed in these patients. Patients presented with jaundice, diarrhea, vomiting, malnutrition, seizures, allergies and more cataracts in the neonatal period. Commonly, Cataract disease is idiopathic origin. Also, patients with cataracts may have an underlying genetic abnormality of galactose metabolism. Elevated levels of galactose and galactose-1-phosphate and absence of GALT activity were diagnosed in the studied patients. Early biochemical and molecular-genetic diagnosis and genetic counseling of patients and their family members are extremely important in the treatment of galactosemia. We selected 25 cataract patients aged 0-45 years and 25 age and sex-matched controls for the study. Blood samples taken from the experimental and control groups, were biochemically and then molecular-genetically analyzed. Mutations Q188R, K285N and N314D were investigated in patients. Of these mutations, only the N314D mutation was detected in two patients. Both heterozygous and homozygous forms of N314D mutation were detected.

The blood count as a compass to navigate in the ever-changing landscape of the carrier state of hemoglobinopathies: a single-center Italian experience.

Approximately 7% of the worldwide population exhibits variations in the globin genes. The recent migration of populations from countries where hemoglobin disorders are endemic has resulted in important epidemiological changes with the diffusion of newly discovered or poorly characterized genetic variants and new combinations and very heterogeneous clinical phenotypes. The aim of our study is to assess the parameters that are more significant in predicting a positive genetic testing outcome for hemoglobinopathies in a pediatric population of patients presenting with anemia or microcythemia, without a definite diagnosis. This study included patients evaluated in our hematological outpatient clinic for anemia and/or microcythemia despite normal ferritin levels. A screening of pathological hemoglobins using high-performance liquid chromatography (HPLC) was performed for the entire population of the study. Subsequently, patients with hemoglobin (Hb) S trait and patients with an HPLC profile compatible with beta thalassemia trait were excluded from the study. Genetic screening tests for hemoglobinopathies were performed on the remaining patients, which involved measuring the red blood cell (RBC) counts, red blood cells distribution width (RDW), reticulocyte count, and mean corpuscular volume of reticulocytes (MCVr). This study evaluated a total of 65 patients, consisting of nine patients with negative genetic analysis results and 56 patients with positive genetic analysis results. The Hb and RDW values in these two groups did not demonstrate statistical significance. On the other hand, there were statistically significant differences observed in the mean corpuscular volume (MCV), RBC count, reticulocyte count, and MCVr between the two groups. Furthermore, in the group of patients with positive genetic test results, specific genetic findings associated with different HPLC results were observed. In particular, 13 patients with positive genetic test results had normal HPLC findings. This study has demonstrated that HPLC, while serving as a valuable first-level test, has some limitations. Specifically, it has been observed that some patients may exhibit a negative HPLC result despite a positive genetic analysis. In addition to the presence of low levels of Hb and HPLC alterations, other parameters could potentially indicate the underlying mutations in the globin genes. Therefore, we propose that the complete blood cell count be utilized as a widely available parameter for conducting targeted genetic analyses to avoid the risk of overlooking rare hemoglobinopathies.

Lessons learned from the first national population-based genetic carrier-screening program for Duchenne muscular dystrophy

PurposeTo summarize the results of first year implementation of pan-ethnic screening testing for Duchenne muscular dystrophy (DMD) and present the ensuing challenges. MethodsData acquisition for this study was performed by retrospective search of Ministry of Health registry for reports of all laboratories performing genetic screening tests. DMD testing was performed by multiplex ligation-dependent probe amplification technology. In case of single-exon deletion, sequencing of the specific exon was performed to rule out underlying single-nucleotide variant. ResultsOf overall 85,737 DMD tests, 82 clinically significant findings were noted (0.095%, or 1:1,046 women). In addition, 80 findings with uncertain clinical significance were detected (0.093%, or 1:1072), as well as 373 cases (0.4%, or 1:230) of single-exon deletions subsequently identified as false positives because of underlying single-nucleotide variant, mostly variants in exon 8 in North African Jewish population, and in exon 48 in Arab Muslim population. ConclusionInterpretation of population-based DMD carrier screening is complex, occasionally requiring additional genetic testing methods and ethical considerations. Multicenter data registry, including ethnic origin and familial segregation in selected cases, is crucial for optimal definition of the results during genetic counseling and informed decisions regarding prenatal testing.

Genetic counseling practices among outpatient obstetric providers in the Northeast

ACOG recommends all pregnant people be offered genetic screening and diagnostic testing regardless of risk factors. Previous studies have demonstrated disparities in referrals for genetic testing by race outside of pregnancy, but little data exists regarding genetic counseling practices during pregnancy. To describe how patient, provider, and practice demographics influence offering diagnostic prenatal genetic testing by outpatient prenatal care providers. This was a multi-center anonymous survey study conducted between October 2021 and March 2022. Outpatient prenatal care providers, including Family Medicine and Obstetric attendings, residents, MFM fellows, Nurse Practitioners, Physician Assistants and Midwives, were surveyed about their genetic counseling practices and practice demographics. The primary outcome was the proportion of respondents who answered "Yes - all patients" to the survey question "Do you offer diagnostic genetic testing to all patients". Secondary outcomes included the association between patient and practice demographics and offering diagnostic testing. Diagnostic testing was defined as chorionic villus sampling (CVS) or amniocentesis. Screening genetic tests were defined as sequential screen, quadruple screen, cell free DNA screening or "other". Chi-square test or Fisher's exact test were used as appropriate. For the outcome answers of diagnostic testing, logistic regression was performed to assess the association between the answer of diagnostic genetic testing and current training level of providers, race/ethnicities, and insurance status variables. Multivariable analysis was used to adjust for confounders. 635 outpatient prenatal care providers across 7 sites were sent the survey. 419 providers responded for a total response rate of 66%. Of the providers who responded, the majority were attendings (44.9%) followed by residents (37.5%). Providers indicated the race, insurance status, and primary language of their patient population. Screening genetic testing was offered by 98% of providers. Per provider report, 37% offered diagnostic testing to all patients, 18% did not offer it at all, and 44% only offered if certain patient factors were present. 54.8% of attendings reported universally offering diagnostic testing. On univariable analysis, residents were less likely to offer diagnostic testing than attendings (OR 0.18 95% CI 0.11, 0.30). Providers who serve Black/Non-Hispanic, Black/Hispanic, and Other/Hispanic patients were less likely to report offering diagnostic testing compared to other patient populations. Providers who served White/Non-Hispanic were more likely to offer diagnostic testing (OR 2.26 95%CI 1.51-3.39). Patient populations who were primarily privately insured were more likely to be offered diagnostic testing compared to primarily publicly insured patients (OR 6.25 95%CI 3.60-10.85). Providers who served a primarily English-speaking population were more likely to offer diagnostic genetic testing than other patient populations (OR 0.43 95%CI 0.26-0.69). On multivariable analysis, the factors that remained significantly associated with offering diagnostic testing included level of training (resident: OR=0.33 95%CI 0.17-0.62, p=0.0006; APP OR=0.34 95%CI 0.15-0.82, p=0.02), having at least 1/3 of the patient population identify as "other-Hispanic" (OR=0.42 95% CI 0.23-0.77, p= 0.005) and having private as compared to public insurance (primarily private insured OR=2.84 95%CI 1.20-6.74, P=0.02). Although offering genetic screening and diagnostic testing to all patients is recommended, no provider group universally offers diagnostic testing. Providers who serve populations from a racial/ethnic minority, those with public insurance, and those whose primary language is not English are less likely to report universally offering diagnostic genetic testing.

The role of noncoding genetic variants in cardiomyopathy.

Cardiomyopathies remain one of the leading causes of morbidity and mortality worldwide. Environmental risk factors and genetic predisposition account for most cardiomyopathy cases. As with all complex diseases, there are significant challenges in the interpretation of the molecular mechanisms underlying cardiomyopathy-associated genetic variants. Given the technical improvements and reduced costs of DNA sequence technologies, an increasing number of patients are now undergoing genetic testing, resulting in a continuously expanding list of novel mutations. However, many patients carry noncoding genetic variants, and although emerging evidence supports their contribution to cardiac disease, their role in cardiomyopathies remains largely understudied. In this review, we summarize published studies reporting on the association of different types of noncoding variants with various types of cardiomyopathies. We focus on variants within transcriptional enhancers, promoters, intronic sites, and untranslated regions that are likely associated with cardiac disease. Given the broad nature of this topic, we provide an overview of studies that are relatively recent and have sufficient evidence to support a significant degree of causality. We believe that more research with additional validation of noncoding genetic variants will provide further mechanistic insights on the development of cardiac disease, and noncoding variants will be increasingly incorporated in future genetic screening tests.

P119 WHEN THE ELECTROCARDIOGRAM CHANGES YOUR DIAGNOSIS

Abstract Sarcomeric hypertrophic cardiomyopathy is among the most common genetic cardiovascular diseases.Clinical,electrocardiographic and echocardiographic evaluation plays a crucial role in the diagnosis and initial framing of the hypertrophic phenotype. A 51–year–old Caucasian man with multiple myeloma,previous autologous transplant,undergoing chemotherapy for disease recurrence,without cardiovascular risk factors or family history of MCV or MCI came to our outpatient clinic for a follow–up visit.At another center,cardiac amyloidosis was diagnosed due to the echocardiogram finding of concentric left ventricular hypertrophy. Patient asymptomatic for angor,NYHAI dyspnea,heart palpitation,syncope,presented with rhythmic cardiac action,2/6 systolic murmur at centrum and tip,no central or peripheral stasis.On ecg sinus bradycardia at fc57 bpm,PR202 msec,high QRS V4–V6 voltages with negative T waves in infero–lateral site,suggestive for left ventricular hypertrophy. On echocardiogram:concentric left ventricular hypertrophy with posterolateral papillary hypertrophy,preserved contractile function,FE 62%,grade I diastolic dysfunction,no signs of elevated filling pressures,left atrium and right ventricle in normal range;tripartite aortic valve in absence of gradients,prolapse of the LAM(A1–A2)with mild grade insufficiency,mild tricuspid insufficiency. At cardiac MRI:non–dilated left ventricle with concentric hypertrophy,maximum thickness 16mm at basal SIV level,apical inferior wall,15mm anterior wall,anterolateral media,apex systolic obliteration 14mm,FE 64%.Right ventricle and atria in normal.T2–STIR sequences tenuous hyperintensity at infero–lateral media wall,inferior apical wall and lateral,increased T2 mapping in relation to myocardial edema. Subendocardial LGE of middle infero–lateral,apical lateral and postero–medial papillary wall,slight increase in native T1 mapping,ECV 27%,picture of sarcomeric hypertrophic heart disease.Holter ecg showed no arrhythmias;at HCM score low risk,no indication for ICD implantation. The patient was undergoing genetic screening test for HCM.The presence of left ventricular hypertrophy may mimic different forms of hypertrophic cardiomyopathy,leading to misdiagnosis or delayed diagnosis.Differential diagnosis,ecg and specific use of imaging tests are of paramount importance.

Post-mortem genetic testing in sudden cardiac death and genetic screening of relatives at risk: lessons learned from a Czech pilot multidisciplinary study

Sudden cardiac death (SCD) might have an inherited cardiac condition background. Genetic testing supports post-mortem diagnosis and screening of relatives at risk. Our aim is to determine the feasibility of a Czech national collaboration group and to establish the clinical importance of molecular autopsy and family screening. From 2016 to 2021, we have evaluated 100 unrelated SCD cases (71.0% males, age: 33.3 (12.8) years). Genetic testing was performed by next-generation sequencing utilizing a panel of 100 genes related to inherited cardiac/aortic conditions and/or whole exome sequencing. According to autopsy, cases were divided into cardiomyopathies, sudden arrhythmic death syndrome, sudden unexplained death syndrome, and sudden aortic death. We identified pathogenic/likely pathogenic variants following ACMG/AMP recommendations in 22/100 (22.0%) of cases. Since poor DNA quality, we have performed indirect DNA testing in affected relatives or in healthy parents reaching a diagnostic genetic yield of 11/24 (45.8%) and 1/10 (10.0%), respectively. Cardiological and genetic screening disclose 83/301 (27.6%) relatives at risk of SCD. Genetic testing in affected relatives as starting material leads to a high diagnostic yield offering a valuable alternative when suitable material is not available. This is the first multidisciplinary/multicenter molecular autopsy study in the Czech Republic which supports the establishment of this type of diagnostic tests. A central coordinator and proper communication among centers are crucial for the success of a collaboration at a national level.