Advances In Genetic Testing Research Articles

Epidemiology and prognosis of obstructive and non-obstructive hypertrophic cardiomyopathy in Finland: a nationwide cohort study

Abstract Background Hypertrophic cardiomyopathy (HCM) is an often hereditary myocardial disease. The Finnish population has a specific genetic background, which may influence and even predispose people to various hereditary diseases. Whilst advances in genetic testing and imaging techniques may have influenced the detection of HCM and associated subtypes, contemporary data on incidence and prevalence remain limited. Purpose This study aimed to evaluate the current trends in the incidence, prevalence, and prognosis of obstructive and non-obstructive HCM in a nationwide cohort in Finland. Methods A population-based registry study was conducted using data from Finnish nationwide healthcare registries (HILMO/avoHILMO) including individuals aged at least 12 years with recorded HCM diagnosis between 2000 and 2021. The incidence was calculated by dividing the number of newly diagnosed HCM patients by the Finnish background population. Furthermore, the mean incidence per age-group was calculated by dividing the sum of age-group specific incidences by the number of age groups. The date and cause of death were obtained from national registries (Statistics Finland). Mortality was computed by dividing the number of deaths by follow-up length. Patients were followed from 2014 to 2021, and incident cases were defined as new diagnoses after 2014. HCM cases were stratified into obstructive HCM and non-obstructive HCM based on ICD-10 codes I42.1 and I42.2, respectively. Results Among 5,834 documented patients with HCM, the overall mean incidence by age-group was 2.64/100,000, with incidence increasing with age, peaking in those aged ≥85 years (6.22/100,000 patient-years [PY]). Annual incidence of obstructive HCM decreased from 2.2 to 1.4/100,000 PY, while non-obstructive HCM increased from 4.6 to 5.4/100,000 PY between 2014 and 2021 (Fig 1). Prevalence of non-obstructive HCM rose from 40 to 56/100,000 PY, while obstructive HCM prevalence remained stable (23-24/100,000 PY). All-cause mortality was 5.5/100 PY, with obstructive and non-obstructive HCM mortality at 5.7 and 4.6/100 PY, respectively. HCM-specific deaths accounted for 16% and 12% of all deaths in patients with non-obstructive and obstructive HCM, respectively. Conclusions This nationwide study in Finland revealed an increasing incidence and prevalence of non-obstructive HCM over time, contrasting with stable rates among patients with obstructive HCM. Incidence and prevalence were strongly age dependent. Non-HCM-related deaths were predominant in both HCM subtypes.

Public’s perception and attitude toward genetic testing in Jazan region

ABSTRACT Background: With the advancements in genetic testing, a differentiated evaluation for susceptibility to diseases is becoming applicable to many disorders. Understanding the circumstances and promoting the widespread use of these tests in the Saudi setting requires understanding public opinion and attitudes. This study aimed to determine the perception and attitudes of the public in the Jazan region to genetic testing. Material and Methods: A cross-sectional survey study of 507 participants was conducted in the Jazan region. The data were collected through an online questionnaire containing demographic information and statements assessing public perceptions and attitudes. Results: Our findings showed that perspectives toward genetic testing, especially premarital and prenatal testing, are generally positive and consistent with previous research. Approximately 79.1% of the participants had a positive attitude toward supporting a compulsory governmental decision of genetic screening before marriage, and 67.3% were willing to perform such testing in the future. More than half of the participants were willing to allow pregnancy termination if there was a higher probability of genetic disease in the baby. In contrast, only 29.6% agreed with the decision to divorce due to the higher probability of genetic disease in their children. The predictors for a positive attitude to genetic testing were nationality, marital status, and monthly income. Conclusion: The results of the present study indicate that there are acceptable perspectives and attitudes toward genetic testing, especially premarital and prenatal testing.

Advancements of the 21st century and Their Implications on Medical Research and Diagnosis

Throughout the 20th century, new research and new demands have led to an increased amount of technology used in medicine. These methods have led to early detection, better context of conditions, increased efficiency, and brighter prospects for the future of medical diagnosis. However, the increasing use of AI and genetics in medicine has called for checks and further clinical trials to determine how ethical these practices might be. The debate surrounding the integration of Artificial Intelligence has created further controversy—that is, what technologies should be used and what technologies should not be used. To determine a solution, certain factors should be considered including the comfort of patients during treatments including advanced technology, the risk factor of integrating AI into procedures, and the efficiency of technology compared to traditional medical practices. For example, imaging technologies such as X-ray and sonography are found to be more comfortable for patients due to their long-standing familiarity, yet their precision and accuracy fall short in comparison to advanced Imaging technologies such as CT, MRI, and PET scans. There has also been discussion of the use of genetic testing such as chromosomal microarrays. Advances in genetic testing have led to the ability to detect conditions in embryos which can be beneficial, but the manipulation of the embryos could raise ethical concerns. Past ethical grey areas, there have been amazing prospects for the future of medicine and these innovations, such as the use of non-invasive testing which is an emerging alternative to traditional surgical methods. Through extensive literary research, this paper considers the multiple aspects that should contribute to deciding to implement technological advancements brought in the 21st Century. By investigating previous integrations of innovations within medicine, this research could envision a risk-free and more ethical approach to advancing medicine with technology.

2023 ESC guidelines for management of cardiomyopathies: short review with implications for the clinical practice in Bulgaria

The 2023 European Society of Cardiology guidelines for the management of cardiomyopathies (CM) provide practical recommendations for diagnosis and treatment. They emphasize on the need for a systematic clinical evaluation beginning with clinical suspicion of CM and using a multiparametric approach that leads to classification of CM into one of five distinct phenotypes. А cardiomyopathy mindset, together with a multidisciplinary approach are crucial. Further investigations, including advanced imaging and genetic testing, are needed to make a phenotype-based etiological diagnosis. Detection of pathogenic genetic variants allows risk stratification of sudden cardiac death, where new recommendations are available regarding primary prevention. Therapeutic options are expanded with the approval of a new class of drugs for the treatment of symptomatic hypertrophic cardiomyopathy with left ventricular outflow tract obstruction. Specific exercise recommendations are given and reproductive issues in patients with CM are addressed. The lack of reimbursement by the National Health Insurance Fund (NHIF) of genetic testing and the severely limited reimbursement of some imaging methods are a significant problem in Bulgaria, which leads to difficulties in implementing the new guidelines.

Personalized Nutrition: Tailoring Dietary Recommendations through Genetic Insights.

Personalized nutrition (PN) represents a transformative approach in dietary science, where individual genetic profiles guide tailored dietary recommendations, thereby optimizing health outcomes and managing chronic diseases more effectively. This review synthesizes key aspects of PN, emphasizing the genetic basis of dietary responses, contemporary research, and practical applications. We explore how individual genetic differences influence dietary metabolisms, thus underscoring the importance of nutrigenomics in developing personalized dietary guidelines. Current research in PN highlights significant gene-diet interactions that affect various conditions, including obesity and diabetes, suggesting that dietary interventions could be more precise and beneficial if they are customized to genetic profiles. Moreover, we discuss practical implementations of PN, including technological advancements in genetic testing that enable real-time dietary customization. Looking forward, this review identifies the robust integration of bioinformatics and genomics as critical for advancing PN. We advocate for multidisciplinary research to overcome current challenges, such as data privacy and ethical concerns associated with genetic testing. The future of PN lies in broader adoption across health and wellness sectors, promising significant advancements in public health and personalized medicine.

Family Planning in Genetic Optic Atrophies in Israel, a Case Series and a Discussion of Ethical Considerations.

Patients with genetic optic atrophies must navigate all stages of life with their visual impairment, including the important milestone of family planning. Advances in genetic testing now allows physicians and affected families to consider medical help with the aim of preventing blindness through preconception, preimplantation, and perinatal methods. This case series presents 4 patients with different genetic optic atrophies (Leber hereditary optic neuropathy [LHON], autosomal dominant optic atrophy, Wolfram syndrome, and papillorenal syndrome) who were followed by the Neuro-Ophthalmology Unit at a tertiary medical center between 2010 and 2023 and were of child-bearing age. The aim of this study was to increase understanding in family planning options for patients with optic atrophies, raise awareness of the solutions available, and provide guidance for clinicians to support their patients. Advances in medicine, genetics, and medical technology allow multidisciplinary teams to assist patients in fulfilling their desire for a genetically healthy offspring. Customized solutions can be designed to meet the specific challenges posed by each type of genetic optic atrophy. The solutions proposed in this series are based on genetic testing done in the parents, which then allows to plan medical and genetic intervention individually. The solutions opted for in this series range from the decision to not have another child until PGD (Preimplantation genetic diagnosis). We describe how genetic advancements have made it possible for patients with the 4 most common hereditary optic atrophies to fulfill their wish to have children without visually threatening genetic mutations. We also review the recent literature on the penetrance of optic atrophy in OA-mutation carriers and raise 2 significant ethical considerations: the reduction of a future life to a non-life-threatening impairment and that of public expenditure for non-life-threatening conditions.

The Genetic Diagnostics of Hemochromatosis: Disparities in Low- Versus High-Income Countries.

This study provides a comprehensive overview of hereditary hemochromatosis (HH), a genetic condition characterized by iron overload due to excessive iron absorption. It elucidates diverse inheritance patterns and clinical manifestations by exploring mutations in critical genes such as HFE (hemochromatosis), HJV (hemojuvelin), HAMP (hepcidin antimicrobial peptide), TfR2 (transferrin receptor 2), and FP (ferroportin). The significance of early screening, diagnosis, and personalized management strategies based on genetic classification is emphasized, particularly in terms of high-income vs. low-income countries. Addressing challenges in diagnosis, genetic testing accessibility, and healthcare disparities, the study highlights the importance of early detection, cost-effective screening strategies, and enhancing healthcare outcomes globally. Advanced genetic testing in high-income countries facilitates early diagnosis and management, reducing complications such as liver disease and cardiomyopathy. In contrast, low-income populations face several barriers, including limited access to genetic testing, high costs, and inadequate healthcare infrastructure. Cost-effective serum ferritin (SF) and transferrin saturation (TS) tests and emerging point-of-care (POC) tests offer affordable diagnostic options for low-resource settings. Additionally, the ongoing development of hepcidin measurement methods holds promise for enhancing diagnostic capabilities. Implementing these strategies can aid healthcare providers in improving global HH management and reducing the burden of iron overload complications. Furthermore, the study underscores the need for public health initiatives to raise awareness about HH, promote routine screenings, and advocate for equitable healthcare policies. Collaborative efforts between governments, healthcare organizations, and research institutions are crucial in addressing the global burden of HH. By fostering international cooperation and resource-sharing, it is possible to bridge the gap between high-income and low-income countries, ensuring all individuals have access to the necessary diagnostic and treatment options. This holistic approach can ultimately lead to better health outcomes and improved quality of life for individuals affected by HH worldwide. This comprehensive examination of HH not only illuminates the genetic and clinical aspects of the condition but also provides a roadmap for addressing the multifaceted challenges associated with its diagnosis and management.

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

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

Advancing Genetic Testing in Kidney Diseases: Report From a National Kidney Foundation Working Group

About 37 million people in the United States have chronic kidney disease, a disease that encompasses diseases of multiple causes. About 10% or more of kidney diseases in adults and about 70% of selected chronic kidney diseases in children are expected to be explained by genetic causes. Despite the advances in genetic testing and an increasing understanding of the genetic bases of certain kidney diseases, genetic testing in nephrology lags behind other medical fields. More understanding of the benefits and logistics of genetic testing is needed to advance the implementation of genetic testing in chronic kidney diseases. Accordingly, the National Kidney Foundation convened a Working Group of experts with diverse expertise in genetics, nephrology, and allied fields to develop recommendations for genetic testing for monogenic disorders and to identify genetic risk factors for oligogenic and polygenic causes of kidney diseases. Algorithms for clinical decision making on genetic testing and a road map for advancing genetic testing in kidney diseases were generated. An important aspect of this initiative was the use of a modified Delphi process to reach group consensus on the recommendations. The recommendations and resources described herein provide support to nephrologists and allied health professionals to advance the use of genetic testing for diagnosis and screening of kidney diseases.

Comprehensive evaluation of the child with global developmental delays or intellectual disability.

Global developmental delay (GDD) and intellectual disability (ID) are relatively common neurodevelopmental disorders that significantly impact affected children, their families, and society. The etiology of GDD/ID is notably diverse, encompassing both genetic and acquired factors. Although the precise cause of most GDD/ID cases remains unclear, an estimated half of all cases can be attributed to genetic factors. Thus, a detailed medical history and comprehensive physical examination remain pivotal for guiding diagnostic investigations into the underlying causes of GDD/ID. Advancements in genetic testing have supplanted traditional methods such as karyotyping and fluorescence in situ hybridization with chromosomal micro arrays, which are now the primary genetic tests for children with idiopathic GDD/ID. Moreover, the evaluation of Fragile X and Rett syndrome should be an integral component of initial diagnostic assessments. In recent years, whole-exome sequencing and whole-genome sequ-encing have emerged as important diagnostic tools for evaluating children with GDD/ID and have substantially enhanced the diagnostic yield rates. Gene therapy has emerged as a promising avenue and is poised to become a cornerstone in addressing various genetic developmental and epilepsy disorders. Early intervention facilitated by a proficient multidisciplinary team can markedly enhance the prognosis and outcomes of GDD/ID, particularly when parents or caregivers are actively engaged in the interventional process. This review discusses risk factors and common underlying causes, explores recent evidence and recommendations for genetic evaluation, and offers management strategies for children with GDD/ID.

Impact of functional gene groups on outcomes after ablation of ventricular tachycardia in patients with inherited left ventricular cardiomyopathy: an international multicentre study

Abstract Background Advances in genetic testing has enabled identification of pathogenic variants of different functional gene groups associated with non-dilated left ventricular cardiomyopathy (NDLCM)/dilated cardiomyopathy (DCM) and ventricular tachycardia (VT). However, there is limited data on the impact of functional groups on VT ablation outcome. Aim We aimed to assess the impact of likely pathogenic/pathogenic variants (LP/Pv) of different functional gene groups on heart failure (HF) outcomes and VT recurrence in patients with NDLCM/DCM after VT ablation. Methods Patients with NDLCM/DCM who underwent genetic testing (next-generation sequencing) and were referred for VT ablation were enrolled at 6 participating centers. Patients were followed for VT recurrence, HF-related adverse outcomes (death, left ventricular assist device [LVAD], or heart transplantation due to HF), and all-cause mortality. Results A total of 239 patients (age 55±14yrs; male n=193; LVEF 40±12%; amiodarone at admission n=103; ICD n=180) were included. LP/Pv were identified in 128 patients (54%), predominantly found in genes encoding sarcomeric (n=36/128, [28%]; titin n=20, myosin binding protein C n=12), followed by nuclear membrane (n=27/128, [22%]; lamin A/C; n=26), desmosomal (n=23/128, [18%]; desmoplakin n=11, plakophilin n=9), cytoskeleton (n=12/128, [9%]; filamin C n=8), and sarcoplasmic reticulum proteins (n=12/128, [9%]; phospholamban n=10). Variants of unknown significance (n=32) were grouped with patients who tested negative. Acute complete ablation success, defined as non-VT inducibility of any sustained monomorphic VT, was achieved in 113 patients (47%), 63 (56%) with LP/Pv. During a median follow-up of 32 months, 108 patients (45%) had VT recurrence, 41 (17%) had HF-related adverse outcomes (death with/without LVAD in 34, LVAD in 2, heart transplantation in 5) and 47 (20%) died. Patients with LP/Pv were more likely to have VT recurrence, HF-related adverse outcomes and had a higher mortality compared to those without (VT, 68 [53%] vs. 40 [36%]; HF-related adverse outcomes, 30 [23%] vs. 11 [10%]; mortality, 30 [23%] vs. 17 [15%]; log-rank, P<0.01 for all). As compared to patients without LP/Pv, those with LP/Pv in genes encoding nuclear membrane or sarcomeric proteins had significantly worse (P<0.01 for both) and those with LP/Pv in genes encoding desmosomal proteins had similar HF and VT recurrence outcomes (Figure). Of interest, patients with LP/Pv in genes encoding cytoskeleton proteins had favorable HF-related adverse outcomes, but worse VT recurrence (P=0.02) compared to those without LP/Pv (Figure). Conclusion In patients with NDLCM/DCM and VT, the impact of LP/Pv on HF and VT-recurrence outcomes after ablation differs across functional groups. Integrating genetic testing in the comprehensive evaluation of patients with NDLCM/DCM undergoing VT ablation may facilitate personalized ablation strategies and early consideration of alternative HF treatments.

#2095 Genetic kidney disease in pregnancy – experience of tertiary referral hospital

Abstract Background and Aims Genetic kidney diseases (GKD) are rarely seen in pregnancy and some diagnosis will only be made during gestation, due to a high proportion of chronic kidney diseases (CKD) of unknown etiology and recent advances in genetic testing. Genetic counseling and, when possible, preimplantation genetic testing (PGT) should be offered pre-pregnancy to this specific CKD population. Method Retrospective analysis of maternal, obstetric and perinatal outcomes of pregnant women with GKD surveilled at Hospital Santa Maria, at the nephro-obstetric clinic from 2011 to 2023. Results We evaluated 34 pregnancies in 28 women, mean maternal age 30±6 years-old [21-37], 89% Caucasian. Molecular genetic testing was performed pre-pregnancy, during and post-pregnancy in 12/19, 2/19 and 5/19 patients, respectively. At baseline, mean serum creatinine (SCr) and proteinuria (Pr) was 1.0±0.9 mg/dL and 222±516 mg/g, with CKD stage 1/2/3/4/5 in 27/2/2/1/2 gestations and chronic hypertension (HTN) in 11/34 pregnancies. Only 1/28 patients performed PGT, while 1/28 patient declined it. De novo or increased Pr occurred in 10/34 gestations and de novo or worsening HTN in 5/34 gestations. Deterioration of renal function occurred in one patient (CKD3) without recovery and one patient (CKD5) induced dialysis 4 months post-pregnancy. Nephrotic Pr developed in 4/34 gestations. One patient (FSGS APOL1) was treated with tacrolimus and low dose steroids. The patient with TSC re-started sirolimus on week 22 to treat severe fetal ventricular rhabdomyoma. Miscarriage occurred in 2 pregnancies. The C section rate was 21,8%. There were 7 preterm deliveries of which 3 before 32 weeks of pregnancy, mainly due to severe preeclampsia. Mean gestational age at delivery was 37,6 ± 4 weeks (26-41), mean birth weight 2756 ± 831 g (560-3835). Eight newborns were admitted to neonatal ICU due prematurity, fetal TSC, and feeding difficulties. Pulmonary hemorrhage and sepsis caused the death of 2 newborns. We found 1 maternal death, due to rupture of a cerebral aneurism 1 month postpartum (PKD patient). Conclusion Our cohort was very heterogenous regarding CKD etiologies, but generally with good kidney function, which allowed overall good obstetric outcomes. Still, maternal, obstetric and fetal complications, namely HTN, Pr, PE and prematurity had an increased incidence compared to pregnancy in healthy patients. This particular population should be approached by an experienced multidisciplinary team in CKD pregnancy care to optimize outcome.

Neonatal perspective on central lymphatic disorders

Lymphatic disorders presenting in the first year of life are difficult to identify and manage given the broad range of underlying etiologies. Neonatal lymphatic disease arising from congenital or acquired conditions results in the abnormal accumulation of lymph fluid in the pleura (chylothorax), peritoneum (chylous ascites) and skin (edema/anasarca). There is also increasing recognition of lymphatic losses through the intestine resulting in protein-losing enteropathy (PLE). While the incidence of lymphatic disorders in neonates is unclear, advances in genetic testing and lymphatic imaging are improving our understanding of the underlying pathophysiology. Despite these advancements, medical management of neonatal lymphatic disorders remains challenging and variable among clinicians.

Somatic Mutations in Surgically Treated Colorectal Liver Metastases: An Overview.

Colorectal cancer is the second most common cause of cancer death in the United States, and up to half of patients develop colorectal liver metastases (CRLMs). Notably, somatic genetic mutations, such as mutations in RAS, BRAF, mismatch repair (MMR) genes, TP53, and SMAD4, have been shown to play a prognostic role in patients with CRLM. This review summarizes and appraises the current literature regarding the most relevant somatic mutations in surgically treated CRLM by not only reviewing representative studies, but also providing recommendations for areas of future research. In addition, advancements in genetic testing and an increasing emphasis on precision medicine have led to a more nuanced understanding of these mutations; thus, more granular data for each mutation are reviewed when available. Importantly, such knowledge can pave the way for precision medicine with the ultimate goal of improving patient outcomes.

Current Issues With Pediatric Cochlear Implantation.

Cochlear implants (CIs) have demonstrated a clear functional benefit in children with severe-to-profound sensorineural hearing loss (SNHL) and thus have gained wide acceptance for treating deafness in the pediatric population. When evaluating young children for cochlear implantation, there are unique considerations beyond the standard issues addressed during surgery in adults. Because of advances in genetic testing, imaging resolution, CI technology, post-implant rehabilitation, and other factors, issues related to CI surgery in children continue to evolve. Such factors have led to changes in candidacy guidelines, vaccine requirements, and lowering of age requirement for surgery. In addition, differences in the anatomy and physiology of infants require special attention to ensure safety when operating on young children. This review summarizes these issues and provides guidance for surgeons treating children with SNHL.

Abstract 814: Bridging the gap: Informal caregivers' access to information on genetic testing for cancer risk

Abstract Introduction: Cancer risk genetic testing (referred to as genetic testing thereafter) benefits patients by allowing them to make informed behavioral and medical decisions to reduce cancer risk and by facilitating surveillance and earlier detection. Informal caregivers, who often serve as primary advocates for those at risk, play a pivotal role in supporting behavioral and medical decisions based on genetic testing information. Assessing caregivers’ knowledge of genetic testing can guide future interventions supporting informed decision-making to ensure that all groups benefit equally from advances in genetic testing. We examined the association between caregiving and knowledge of genetic testing as well as other individual and socioeconomic factors. Methods: Secondary data analysis was conducted using the 2020 Health Information National Trends Survey (HINTS 5 Cycle 4). HINTS is a nationally representative survey of adults in the civilian non-institutionalized US population. Exposure variable was caregiving (yes/no) assessed with the question “Are you currently caring for or making health care decisions for someone with a medical, behavioral, disability, or other condition?”. The outcome variable was genetic testing knowledge (yes/no) assessed with the question “have you heard of high-risk cancer genetic testing - e.g., BRCA 1/2". Weighted, multivariable logistic regression was used to estimate the association between caregiving and genetic testing knowledge adjusting for age, gender, race/ethnicity, marital status, education level, having a regular provider, rural-urban residence, and self-reported general health status. Results: A total of 3,136 participants aged ≥18 were included in the study, of whom 16.4% were caregivers and 35.9% had heard of genetic testing. In the adjusted analysis, there was no statistically significant difference between caregivers and non-caregivers in relation to genetic testing knowledge (P=0.7881). However, respondents who were ≥65 years old (aOR=0.54, 95% CI: 0.40-0.72) were less likely to have heard about genetic testing compared to those aged 18-49, as were respondents who had no regular provider (aOR=0.71, 95% CI: 0.53-0.95) compared to those with a regular provider. Compared to non-Hispanic White respondents, non-Hispanic Black (aOR=0.45, 95% CI: 0.31-0.66) or Hispanic respondents (aOR=0.44, 95% CI: 0.29-0.68) were less likely to have heard about genetic testing. Female respondents (aOR=2.02, 95% CI: 1.55-2.61) were twice as likely to have heard about genetic testing than their male counterparts. Conclusions: We found that about a third of Americans had heard about genetic testing; patients who were younger, female, White, and those who had access to a regular provider were more likely to be aware of testing. Interventions targeting under-resourced caregivers are urgently needed to promote equity in genetic testing and its benefits. Citation Format: Eric Adjei Boakye, Pranali G. Patel, Chaitali S. Dagli, Sarah Wagoner, Mrudula Nair, Nosayaba Osazuwa-Peters, Veronica Bernacchi, Samantha H. Tam. Bridging the gap: Informal caregivers' access to information on genetic testing for cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 814.

Genetic testing for unexplained epilepsy: A review of diagnostic approach, benefits, and referral algorithm

In the last several decades, advances in genetic testing have transformed the diagnostic and therapeutic approach to pediatric epilepsy. However, the interpretation of these genetic tests often requires expert analysis and counseling. For this reason, as our molecular understanding of the linkages between abnormal cerebral physiology and genetics has grown, so too has the field of clinical epilepsy genetics. Here we explore recent advances in genetic testing, describe the benefits of genetic testing in epilepsy, and provide a practice guideline for testing and referrals to specialized epilepsy genetics centers, highlighting the Epilepsy NeuroGenetics Initiative (ENGIN) Clinic and the Center for Epilepsy and Neurodevelopmental Disorders (ENDD) at the Children's Hospital of Philadelphia as an illustration of such a specialized center.

The Genetics of Tuberous Sclerosis Complex and Related mTORopathies: Current Understanding and Future Directions.

The mechanistic target of rapamycin (mTOR) pathway serves as a master regulator of cell growth, proliferation, and survival. Upregulation of the mTOR pathway has been shown to cause malformations of cortical development, medically refractory epilepsies, and neurodevelopmental disorders, collectively described as mTORopathies. Tuberous sclerosis complex (TSC) serves as the prototypical mTORopathy. Characterized by the development of benign tumors in multiple organs, pathogenic variants in TSC1 or TSC2 disrupt the TSC protein complex, a negative regulator of the mTOR pathway. Variants in critical domains of the TSC complex, especially in the catalytic TSC2 subunit, correlate with increased disease severity. Variants in less crucial exons and non-coding regions, as well as those undetectable with conventional testing, may lead to milder phenotypes. Despite the assumption of complete penetrance, expressivity varies within families, and certain variants delay disease onset with milder neurological effects. Understanding these genotype-phenotype correlations is crucial for effective clinical management. Notably, 15% of patients have no mutation identified by conventional genetic testing, with the majority of cases postulated to be caused by somatic TSC1/TSC2 variants which present complex diagnostic challenges. Advancements in genetic testing, prenatal screening, and precision medicine hold promise for changing the diagnostic and treatment paradigm for TSC and related mTORopathies. Herein, we explore the genetic and molecular mechanisms of TSC and other mTORopathies, emphasizing contemporary genetic methods in understanding and diagnosing the condition.

PKHD1L1, a gene involved in the stereocilia coat, causes autosomal recessive nonsyndromic hearing loss

Identification of genes associated with nonsyndromic hearing loss is a crucial endeavor given the substantial number of individuals who remain without a diagnosis after even the most advanced genetic testing. PKHD1L1 was established as necessary for the formation of the cochlear hair-cell stereociliary coat and causes hearing loss in mice and zebrafish when mutated. We sought to determine if biallelic variants in PKHD1L1 also cause hearing loss in humans. Exome sequencing was performed on DNA of four families segregating autosomal recessive nonsyndromic sensorineural hearing loss. Compound heterozygous p.[(Gly129Ser)];p.[(Gly1314Val)] and p.[(Gly605Arg)];p[(Leu2818TyrfsTer5)], homozygous missense p.(His2479Gln) and nonsense p.(Arg3381Ter) variants were identified in PKHD1L1 that were predicted to be damaging using in silico pathogenicity prediction methods. In vitro functional analysis of two missense variants was performed using purified recombinant PKHD1L1 protein fragments. We then evaluated protein thermodynamic stability with and without the missense variants found in one of the families and performed a minigene splicing assay for another variant. In silico molecular modeling using AlphaFold2 and protein sequence alignment analysis were carried out to further explore potential variant effects on structure. In vitro functional assessment indicated that both engineered PKHD1L1 p.(Gly129Ser) and p.(Gly1314Val) mutant constructs significantly reduced the folding and structural stabilities of the expressed protein fragments, providing further evidence to support pathogenicity of these variants. Minigene assay of the c.1813G>A p.(Gly605Arg) variant, located at the boundary of exon 17, revealed exon skipping leading to an in-frame deletion of 48 amino acids. In silico molecular modeling exposed key structural features that might suggest PKHD1L1 protein destabilization. Multiple lines of evidence collectively associate PKHD1L1 with nonsyndromic mild–moderate to severe sensorineural hearing loss. PKHD1L1 testing in individuals with mild–moderate hearing loss may identify further affected families.

Physiological Appetite Regulation and Bariatric Surgery.

Obesity remains a common metabolic disorder and a threat to health as it is associated with numerous complications. Lifestyle modifications and caloric restriction can achieve limited weight loss. Bariatric surgery is an effective way of achieving substantial weight loss as well as glycemic control secondary to weight-related type 2 diabetes mellitus. It has been suggested that an anorexigenic gut hormone response following bariatric surgery contributes to weight loss. Understanding the changes in gut hormones and their contribution to weight loss physiology can lead to new therapeutic treatments for weight loss. Two distinct types of neurons in the arcuate hypothalamic nuclei control food intake: proopiomelanocortin neurons activated by the anorexigenic (satiety) hormones and neurons activated by the orexigenic peptides that release neuropeptide Y and agouti-related peptide (hunger centre). The arcuate nucleus of the hypothalamus integrates hormonal inputs from the gut and adipose tissue (the anorexigenic hormones cholecystokinin, polypeptide YY, glucagon-like peptide-1, oxyntomodulin, leptin, and others) and orexigeneic peptides (ghrelin). Replicating the endocrine response to bariatric surgery through pharmacological mimicry holds promise for medical treatment. Obesity has genetic and environmental factors. New advances in genetic testing have identified both monogenic and polygenic obesity-related genes. Understanding the function of genes contributing to obesity will increase insights into the biology of obesity. This review includes the physiology of appetite control, the influence of genetics on obesity, and the changes that occur following bariatric surgery. This has the potential to lead to the development of more subtle, individualised, treatments for obesity.