Genetic Conditions Research Articles

‘This has given me the peace of mind I needed’: ethnographic insights into Barrett’s oesophagus screening using the capsule sponge test

In 2021 and 2022, researchers carried out an implementation trial that considered how the capsule sponge test might be used to screen for Barrett’s oesophagus using a mobile clinic in...

Progerin Can Induce DNA Damage in the Absence of Global Changes in Replication or Cell Proliferation.

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by features of accelerated aging, and individuals with HGPS seldom live beyond their mid-teens. The syndrome is commonly caused by a point mutation in the LMNA gene which codes for lamin A and its splice variant lamin C, components of the nuclear lamina. The mutation causing HGPS leads to production of a truncated, farnesylated form of lamin A referred to as "progerin." Progerin is also expressed at low levels in healthy individuals and appears to play a role in normal aging. HGPS is associated with an accumulation of genomic DNA double-strand breaks (DSBs) and alterations in the nature of DSB repair. The source of DSBs in HGPS is often attributed to stalling and subsequent collapse of replication forks in conjunction with faulty recruitment of repair factors to damage sites. In this work, we used a model system involving immortalized human cell lines to investigate progerin-induced genomic damage. Using an immunofluorescence approach to visualize phosphorylated histone H2AX foci which mark sites of genomic damage, we report that cells engineered to express progerin displayed a significant elevation of endogenous damage in the absence of any change in the cell cycle profile or doubling time of cells. Genomic damage was enhanced and persistent in progerin-expressing cells treated with hydroxyurea. Overexpression of wild-type lamin A did not elicit the outcomes associated with progerin expression. Our results show that DNA damage caused by progerin can occur independently from global changes in replication or cell proliferation.

Variants in HCFC1 and MN1 genes causing intellectual disability in two Pakistani families

BackgroundIntellectual disability (ID) is a neurodevelopmental condition affecting around 2% of children and young adults worldwide, characterized by deficits in intellectual functioning and adaptive behavior. Genetic factors contribute to the development of ID phenotypes, including mutations and structural changes in chromosomes. Pathogenic variants in the HCFC1 gene cause X-linked mental retardation syndrome, also known as Siderius type X-linked mental retardation. The MN1 gene is necessary for palate development, and mutations in this gene result in a genetic condition called CEBALID syndrome.MethodsExome sequencing was used to identify the disease-causing variants in two affected families, A and B, from various regions of Pakistan. Affected individuals in these two families presented ID, developmental delay, and behavioral abnormalities. The validation and co-segregation analysis of the filtered variant was carried out using Sanger sequencing.ResultsIn an X-linked family A, a novel hemizygous missense variant (c.5705G > A; p.Ser1902Asn) in the HCFC1 gene (NM_005334.3) was identified, while in family B exome sequencing revealed a heterozygous nonsense variant (c.3680 G > A; p. Trp1227Ter) in exon-1 of the MN1 gene (NM_032581.4). Sanger sequencing confirmed the segregation of these variants with ID in each family.ConclusionsThe investigation of two Pakistani families revealed pathogenic genetic variants in the HCFC1 and MN1 genes, which cause ID and expand the mutational spectrum of these genes.

Qatar’s genetic counseling landscape: Current insights and future prospects

Genetic counseling is a dynamic and rapidly growing field. In Qatar, the significance of genetic counseling is underscored by the distinctive demographic characteristics of the population, including elevated rates of consanguinity and larger family sizes, contributing to the increased incidence of many genetic conditions. This emphasizes the crucial role of genetic counseling in addressing the specific needs of the community. Over the past decade, key health care institutions in Qatar, such as Hamad Medical Corporation and Sidra Medicine, have significantly expanded genetic counseling services encompassing premarital, reproductive, prenatal, pediatric, adult, and cancer care. This multifaceted approach reflects Qatar’s health care system’s commitment to addressing various aspects of genetic health and well-being across different life stages.A pivotal milestone in the field’s development in Qatar was the establishment of a genetic counseling master’s program at Qatar University in 2018, showcasing the country’s dedication to fostering indigenous expertise in genetic counseling with the necessary competencies and cultural sensitivity to address the unique genetic counseling needs of the population. The recognition of genetic counseling as a profession and the licensure by the Ministry of Public Health in Qatar is another key achievement to ensure the high quality of service and protection of the profession. Contributing to global genetic knowledge, various academic and research entities in Qatar are conducting genetic/genomic/genetic counseling research toward advancing precision medicine in the country, and initiatives such as the Qatar Biobank and Qatar Genome Program have played a major role in catalyzing these efforts.

Molecular changes underlying pulmonary emphysema and chronic bronchitis in Chronic Obstructive Pulmonary Disease: An updated review.

The aim of this review is to update and synthesize the molecular mechanisms that lead to the heterogeneous effect on tissue remodeling observed in the two most important clinical phenotypes of chronic obstructive pulmonary disease (COPD), pulmonary emphysema (PE) and chronic bronchitis (CB). Clinical and experimental evidence suggests that this heterogeneous response to promote PE, CB, or both, is related to differentiated genetic, epigenetic, and molecular conditions. Specifically, a tendency toward PE could be related to a variant in the DSP gene, SIRT1 downregulation, macrophage polarization to M1, as well as the involvement of the noncanonical Wnt5A signaling pathway, among other alterations. Additionally, in advanced stages of COPD, PE development is potentiated by dysregulations in autophagy, which promotes senescence and subsequently cell apoptosis, through exacerbated inflammasome activation and release of caspases. On the other hand, CB or the pro-fibrotic phenotype could be potentiated by the downregulated activity of HDAC2, the activation of the TGF-β/Smad or Wnt/β-catenin signaling pathways, macrophage polarization to M2, upregulation of TIMP-1, and/or the presence of the epithelial-mesenchymal transition (EMT) mechanism. Interestingly, the upregulated activity of MMPs, especially MMP-9, is widely involved in the development of both phenotypes. Furthermore, MMP-9 and MMP-12 enhance the severity, perpetuation, and exacerbation of COPD, as well as the development of autoimmunity in this disease.

Vigorous Exercise in Patients with Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy is a genetic heart condition occurring in up to 1 in 200 patients in the United States, many of whom are young and otherwise healthy. This condition puts those affected at increased risk for adverse cardiac outcomes, including sudden cardiac arrest and death, with particular concern for this to occur during exercise and other forms of exertion. Recent studies aimed at evaluating the risk of exercise in hypertrophic cardiomyopathy patients have suggested that moderate and even vigorous exercise may be safe for certain patients. Clinical guidelines are changing to reflect this recent information and to encourage a shared decision-making approach, which can allow more hypertrophic cardiomyopathy patients to participate in health-promoting exercise activities.

Genetic susceptibility to neurodevelopmental conditions associates with neonatal DNA methylation patterns in the general population: an individual participant data meta-analysis.

Autism spectrum disorder (ASD), attention-deficit/hyperactivity disorder (ADHD), and schizophrenia (SCZ) are highly heritable and linked to disruptions in foetal (neuro)development. While epigenetic processes are considered an important underlying pathway between genetic susceptibility and neurodevelopmental conditions, it is unclear (i) whether genetic susceptibility to these conditions is associated with epigenetic patterns, specifically DNA methylation (DNAm), already at birth; (ii) to what extent DNAm patterns are unique or shared across conditions, and (iii) whether these neonatal DNAm patterns can be leveraged to enhance genetic prediction of (neuro)developmental outcomes. We conducted epigenome-wide meta-analyses of genetic susceptibility to ASD, ADHD, and schizophrenia, quantified using polygenic scores (PGSs) on cord blood DNAm, using four population-based cohorts (n pooled=5,802), all North European. Heterogeneity statistics were used to estimate overlap in DNAm patterns between PGSs. Subsequently, DNAm-based measures of PGSs were built in a target sample, and used as predictors to test incremental variance explained over PGS in 130 (neuro)developmental outcomes spanning birth to 14 years. In probe-level analyses, SCZ-PGS associated with neonatal DNAm at 246 loci (p<9×10-8), predominantly in the major histocompatibility complex. Functional characterization of these DNAm loci confirmed strong genetic effects, significant blood-brain concordance and enrichment for immune-related pathways. 8 loci were identified for ASD-PGS (mapping to FDFT1 and MFHAS1), and none for ADHD-PGS. Regional analyses indicated a large number of differentially methylated regions for all PGSs (SCZ-PGS: 157, ASD-PGS: 130, ADHD-PGS: 166). DNAm signals showed little overlap between PGSs. We found suggestive evidence that incorporating DNAm-based measures of genetic susceptibility at birth increases explained variance for several child cognitive and motor outcomes over and above PGS. Genetic susceptibility for neurodevelopmental conditions, particularly schizophrenia, is detectable in cord blood DNAm at birth in a population-based sample, with largely distinct DNAm patterns between PGSs. These findings support an early-origins perspective on schizophrenia. HorizonEurope; European Research Council.

Multidimensional and Longitudinal Impact of a Genetic Diagnosis for Critically Ill Infants.

Many genetic conditions present in the neonatal intensive care unit (NICU), where a diagnostic evaluation is pursued. However, understanding of the impact of a genetic diagnosis on clinical outcomes and health-related quality of life for these infants remains incomplete. We therefore evaluated parent-reported outcomes complemented by clinical outcomes measures over one year for a cohort of infants in the NICU undergoing genetic evaluation. Prospective cohort study evaluating outcomes after genetics consultation in a level IV NICU via parent-report and electronic medical records (EMR) review. Eligible infants were genetically undiagnosed at enrollment. Parent surveys were administered at baseline and three, six-, and 12-months following enrollment and assessed genetic testing utility as well as parent-reported infant health-related quality of life using the Infant Toddler Quality of Life Questionnaire. 110 infant-parent pairs were enrolled. Infants had a median age at enrollment of 15 days (interquartile range 8-37.75). At baseline, 74% (81/110) of parents endorsed high importance of finding a genetic diagnosis, but perceived importance significantly decreased over time. Over the study period, 38 infants received a molecular diagnosis per parent report, though this was discordant with EMR review. Identification of a diagnosis did not significantly impact health-related quality of life across most domains, which was lower overall than population norms. A genetic diagnosis is highly desired by parents in the NICU, though waning interest over time for undiagnosed families may reflect parental emotional adaptation and acceptance. Additional supports are needed to improve perceived quality of life.

Exome Sequencing Identifies Carriers of the Autosomal Dominant Cancer Predisposition Disorders Beyond Current Practice Guideline Recommendations.

The autosomal dominant cancer predisposition disorders hereditary breast and ovarian cancer (HBOC) and Lynch syndrome (LS) are genetic conditions for which early identification and intervention have a positive effect on the individual and public health. The goals of this study were to determine whether germline genetic screening using exome sequencing could be used to efficiently identify carriers of HBOC and LS. Participants were recruited from three geographically and racially diverse sites in the United States (Rochester, MN; Phoenix, AZ; Jacksonville, FL). Participants underwent Exome+ sequencing (Helix Inc, San Mateo, CA) and return of results for specific genetic findings: HBOC (BRCA1 and BRCA1) and LS (MLH1, MSH2, MSH6, PMS2, and EPCAM). Chart review was performed to collect demographics and personal and family cancer history. To date, 44,306 participants have enrolled in Tapestry. Annotation and interpretation of all variants in genes for HBOC and LS resulted in the identification of 550 carriers (prevalence, 1.24%), which included 387 with HBOC (27.2% BRCA1, 42.8% BRCA2) and 163 with LS (12.3% MSH6, 8.8% PMS2, 4.5% MLH1, 3.8% MSH2, and 0.2% EPCAM). More than half of these participants (52.1%) were newly diagnosed carriers with HBOC and LS. In all, 39.2% of HBOC/LS carriers did not satisfy National Comprehensive Cancer Network (NCCN) criteria for genetic evaluation. NCCN criteria were less commonly met in underrepresented minority populations versus self-reported White race (51.5% v 37.5%, P = .028). Our results emphasize the need for wider utilization of germline genetic sequencing for enhanced screening and detection of individuals who have LS and HBOC cancer predisposition syndromes.

Rapid genomic testing in critically ill pediatric patients: Genetic counseling lessons from a national program

Genetic counselors (GCs) face unique challenges in the acute care setting. Acute care environments—such as neonatal and pediatric intensive care units—are characterized by urgency, complexity, and rapid decision making. These settings require GCs to navigate a delicate balance between addressing the immediate clinical needs of patients and providing comprehensive genetic information to families, while demanding adaptation of existing skills for practice.Rapid genomic testing (rGT) is increasingly becoming standard of care in acute care. GCs are well placed to support families through the rGT process. Despite this, there is a lack of consistency in the provision of comprehensive acute care genetic counseling globally and a subsequent need for professional guidance in this area.The Acute Care Genomics study piloted a national approach to delivering rGT for infants and children admitted to intensive care units in Australia with suspected genetic conditions between 2018 and 2022. GCs from across Australia were involved in both pre- and post-test counseling for the families of these critically unwell children. Based on our collective experience of delivering this national rGT program, this article provides a discussion of common challenges for health professionals new to delivering rGT in intensive care. We share some practical solutions and make recommendations for supporting families in this area of practice.

A novel in vitro cell model of the proteinase/antiproteinase balance observed in alpha-1 antitrypsin deficiency.

Background: Alpha-1 antitrypsin deficiency (AATD) is a genetic condition resulting from mutations in the alpha-1 antitrypsin (AAT) protein, a major systemic antiproteinase, resulting in reduced/no release of AAT, disrupting the proteinase/antiproteinase balance. A sustained imbalance can cause structural changes to the lung parenchyma, leading to emphysema. Predicting and assessing human responses to potential therapeutic candidates from preclinical animal studies have been challenging. Our aims were to develop a more physiologically relevant in vitro model of the proteinase/antiproteinase balance and assess whether the data generated could better predict the efficacy of pharmacological candidates to inform decisions on clinical trials, together with expected biomarker responses. Methods: We developed an in vitro model assessing the proteinase/antiproteinase balance by the changes in the fibrinogen cleavage products of neutrophil elastase (NE) and proteinase 3 (PR3). This allowed the assessment of physiological and pharmaceutical neutrophil serine proteinase (NSP) inhibitors to determine the putative threshold at which the maximal effect is achieved. Results: AAT significantly reduced NE and PR3 activity footprints, with the maximal reduction achieved at concentrations above 10μM. The inhibitor MPH966 alone also significantly reduced NE footprint generation in a concentration-dependent manner, leveling out above 100nM but had no effect on the PR3 footprint. At levels of AAT consistent with AATD, MPH966 had an additive effect, reducing the NE activity footprint more than either inhibitor alone. Conclusion: Our results support an inhibitor threshold above which the activity footprint generation appears resistant to increasing dosage. Our model can support the testing of inhibitors, confirming activity biomarkers as indicators of likely pharmaceutical efficacy, the assessment of NSP activity in the pathophysiology of emphysema, and the likely function of biological or pharmacological inhibitors in disease management.

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.

Physician- and patient-reported outcomes by hereditary angioedema type: Data from a real-world study.

Background: Hereditary angioedema (HAE) is a rare genetic condition characterized by painful and often debilitating swelling attacks. Little is known about the differences in outcomes between patients with HAE types I or II (type I: HAE caused by C1 esterase inhibitor deficiency; type II: HAE caused by C1 esterase inhibitor dysfunction), with decreased or dysfunctional C1 esterase inhibitor (C1-INH), and those with normal C1-INH (nC1-INH-HAE). Objective: To compare physician- and patient-reported real-world outcomes in patients with HAE types I/II versus patients with nC1-INH-HAE. Methods: Data were drawn from the Adelphi HAE Disease Specific ProgrammeTM a real-world, cross-sectional survey of HAE-treating physicians and their patients in the United States conducted between July and November 2021. Physicians reported patient disease activity and severity, and recent attack history. Patient-reported outcomes were collected. Bivariate tests used were either the Student's t-test, the Fisher exact test, or Mann-Whitney U test. Results: Physicians (N = 67) provided data on 368 patients (92.4% HAE types I/II and 7.6% nC1-INH-HAE). Physicians reported that a higher proportion of patients with nC1-INH-HAE had moderate or high disease activity and moderate or severe disease severity both at diagnosis and at data collection versus those with HAE types I/II. Patients with nC1-INH-HAE versus patients with HAE types I/II experienced increased attack severity (34.6% versus 4.4%) and hospitalization rate during the most recent attack (39.3% versus 6.6%), and reported lower health status and quality of life, via the European Quality of Life 5 Dimension 5 Level (US tariff) and Angioedema Quality of Life, respectively. On average, 25% of the patients with nC1-INH-HAE reported absenteeism and work or activity impairment due to HAE compared with 2.7% of patients with HAE types I/II. Both patient groups reported improvements in disease activity and severity from diagnosis to the time of data collection. Conclusion: These real-world findings suggest that patients with nC1-INH-HAE have increased disease activity and severity, and experience greater impairment to their quality of life, work, and daily functioning than patients with HAE types I/II. Powered statistical analyses are required to confirm these findings.

A Subject Review on Application of Analytical Chemistry in the Mitochondrial Medicine

Understanding energy metabolism and intracellular energy transmission requires knowledge of the function and structure of the mitochondria. Issues with mitochondrial morphology, structure, and function are the most prevalent symptoms. They can damage organs such as the heart, brain, and muscle due to a variety of factors, such as oxidative damage, incorrect metabolism of energy, or genetic conditions. The control of cell metabolism and physiology depends on functional connections between mitochondrial and biological surroundings. Therefore, it is essential to research mitochondria in situ or in vivo without isolating them from their surrounding biological environment. Finding and spotting abnormal alterations in mitochondria is the primary research technique for understanding mitochondrial illnesses. The purpose of this review is to collect original studies and papers describing a variety of analytical chemistry tasks carried out in mitochondria. Analytical chemistry is essential to the biological and medical sciences. Several analytical methods have been used in this field, such as chromatographic, spectroscopic, spectrophotometric, electrochemical analysis, and electrospray ionization mass spectrometry. While spectroscopic techniques in particular have yielded important information in certain cases, the nature of these techniques nevertheless limits the information that can be collected. Mass spectrometry may, however, produce incredibly detailed datasets.

Unprecedented report: First female monozygotic twins as carriers of Hutchinson-Gilford progeria syndrome

Hutchinson-Gilford Progeria Syndrome (HGPS) is a rare genetic condition characterized by premature aging resulting from an autosomal mutation in the LMNA gene. This article presents a groundbreaking instance of the first female monozygotic twins affected by HGPS, originating from Brazil, highlighting the exceptional nature of this case.

Unveiling Cystic Fibrosis: Causes, Symptoms, Complications and Treatment Options

Cystic fibrosis is a progressive genetic condition causing thick, sticky mucus buildup in organs like the lungs and digestive system. Cystic fibrosis occurs due to the mutation in the Cystic Fibrosis Transmembrane conductance Regulator(CFTR) gene inherited from both parents. Symptoms of cystic fibrosis vary and can include chronic cough, wheezing, greasy stool, lung infection, and poor growth. The Sweat Test is used to diagnose Cystic Fibrosis. It checks for the amount of chloride in one's sweat. While there's no cure for cystic fibrosis, treatment focuses on symptom management, such as ensuring clear airways and maintaining proper nutrition through medications, therapies, and sometimes surgery.

Approximating facial expression effects on diagnostic accuracy via generative AI in medical genetics.

Artificial intelligence (AI) is increasingly used in genomics research and practice, and generative AI has garnered significant recent attention. In clinical applications of generative AI, aspects of the underlying datasets can impact results, and confounders should be studied and mitigated. One example involves the facial expressions of people with genetic conditions. Stereotypically, Williams (WS) and Angelman (AS) syndromes are associated with a "happy" demeanor, including a smiling expression. Clinical geneticists may be more likely to identify these conditions in images of smiling individuals. To study the impact of facial expression, we analyzed publicly available facial images of approximately 3500 individuals with genetic conditions. Using a deep learning (DL) image classifier, we found that WS and AS images with non-smiling expressions had significantly lower prediction probabilities for the correct syndrome labels than those with smiling expressions. This was not seen for 22q11.2 deletion and Noonan syndromes, which are not associated with a smiling expression. To further explore the effect of facial expressions, we computationally altered the facial expressions for these images. We trained HyperStyle, a GAN-inversion technique compatible with StyleGAN2, to determine the vector representations of our images. Then, following the concept of InterfaceGAN, we edited these vectors to recreate the original images in a phenotypically accurate way but with a different facial expression. Through online surveys and an eye-tracking experiment, we examined how altered facial expressions affect the performance of human experts. We overall found that facial expression is associated with diagnostic accuracy variably in different genetic conditions.

Variegated overexpression of chromosome 21 genes reveals molecular and immune subtypes of Down syndrome

Individuals with Down syndrome, the genetic condition caused by trisomy 21, exhibit strong inter-individual variability in terms of developmental phenotypes and diagnosis of co-occurring conditions. The mechanisms underlying this variable developmental and clinical presentation await elucidation. We report an investigation of human chromosome 21 gene overexpression in hundreds of research participants with Down syndrome, which led to the identification of two major subsets of co-expressed genes. Using clustering analyses, we identified three main molecular subtypes of trisomy 21, based on differential overexpression patterns of chromosome 21 genes. We subsequently performed multiomics comparative analyses among subtypes using whole blood transcriptomes, plasma proteomes and metabolomes, and immune cell profiles. These efforts revealed strong heterogeneity in dysregulation of key pathophysiological processes across the three subtypes, underscored by differential multiomics signatures related to inflammation, immunity, cell growth and proliferation, and metabolism. We also observed distinct patterns of immune cell changes across subtypes. These findings provide insights into the molecular heterogeneity of trisomy 21 and lay the foundation for the development of personalized medicine approaches for the clinical management of Down syndrome.

Genetic-epigenetic aspects of infertility in women with long-COVID-19

The aim of the study is to determine the genetic and epigenetic features of infertile patients with long-term COVID-19 in order to clarify the risk factors for the failure of assisted reproductive technologies (ART) use. Materials and methods. The MTHFR (C677T, A1298С), RFC-1 (G80A) and BHMT (G742A) gene polymorphisms and the methylation of ESR1 gene was performed. 40 patients (main group) with infertility due to long-term COVID-19 were examined: the subgroup 1 - 25 women in whom the use of ART was ineffective, the subgroup 2 - 15 patients with effective use of ART. The control was taken from literary sources: for RFC (G80A), MTHFR (C677T) and MTHFR (A1298C) polymorphisms - 35 Ukrainian women without infertility and reproductive losses; for BHMT (G742A) - 60 people of the Ukrainian population. The methods of variational statistics were used, in particular the Fisher test with a significance level of p&lt;0.05. Results. Patients of the main group have a higher frequency of the homozygous genotype of the MTHFR gene polymorphism (C677T) on the mutant T allele (20.0% vs. 3.2%; p&lt;0.05). When ART is unsuccessful, the TT genotype is 4 times greater (28.0% vs. 6.7%; p&lt;0.05). A study by genotypes of MTHFR polymorphism (A1298C) did not reveal a significant difference. Patients of the main group `have a higher frequency of the mutant allele A of the RFC gene (G80A) (80.0% vs. 51.4%; p&lt;0.05). No significant difference was found depending on the success rate of ART. The frequency of BHMT gene polymorphism (G742A) in the main group did not differ from that in the Ukrainian population, however, in the case of unsuccessful ART, it was observed less often and only in the heterozygous variant (40.0% vs. 66.6%; p&lt;0.05). The analysis of pairwise intergenic interaction revealed the highest frequency of the combination of AAGA for the MTHFR (A1298C)+BHMT (G742A) pair - 35.0% and GAAA for the RFC (G80A)+MTHFR (A1298C) pair - 30.0% in the main group. Hypermethylation of the promoter region of the ESR1 gene is observed in 20 (50.0%) patients of the main group: in 17 (68.0%) women of the subgroup 1 versus 3 (20.0%) women of the subgroup 2 (p&lt;0.05). Conclusions. The genetic and epigenetic conditioning of the success of ART programs in infertility associated with long-term COVID-19 has been revealed, which opens up new diagnostic and therapeutic opportunities for identifying factors predisposing to unsuccessful ART treatment and increasing the effectiveness of such treatment by correcting disorders of folic acid metabolism, hyperhomocysteinemia and the estrogens receptor apparatus. The research was carried out in accordance with the principles of the Declaration of Helsinki. The research protocol was approved by the Local Ethics Committee of the institution mentioned in the work. Informed consent of the women was obtained for the research. The authors declare no conflict of interest.

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.