Burden Of Genetic Disease Research Articles

Genetic Testing Practices and Pathological Assessments in End Stage Heart Failure Patients Undergoing Heart Transplantation and Left Ventricular Assist Device

BackgroundGenetic cardiomyopathies (CM) are increasingly recognized as causes of end-stage heart failure (ESHF). Identification of a genetic etiology in ESHF has important prognostic and family implications. However, genetic testing practices are understudied in ESHF patients. MethodsThis single-center, retrospective study included consecutive ESHF patients who underwent heart transplantation (HT) or left ventricular assist device (LVAD) from 2018 to 2023. Data, including genetic testing and pathology reports, were collected from the electronic medical record. Analyses of demographic and clinical characteristics were stratified by genetic testing completion and presence of clinically actionable variant. Logistic regression was performed to evaluate for associations between histology findings and genetic variants. ResultsA total of 529 adult patients (mean age 57 years) were included in the study and were predominantly male (79%, 422/529) and non-white (61%, 322/529). Genetic testing was performed in 54% (196/360) of patients with either non-ischemic or mixed CM. A clinically actionable result was identified in 36% (70/196) of patients, of which, only 43% (30/70) had a genetic counselor referral. The most common genetic variants were TTN (32%, 24/75), MYBPC3 (13%, 10/75), and TTR (11%, 8/75). Clinically actionable variants were identified in patients with known heart failure precipitators, such as alcohol use. In multivariable analysis, presence of interstitial fibrosis, specifically diffuse, on pathology was significantly associated with a clinically actionable variant (aOR 2.29, 95% CI [1.08-4.86], p = 0.03). ConclusionESHF patients with non-ischemic or mixed CM undergoing advanced therapies had a low uptake of genetic services, including testing and counselors, despite a high burden of genetic disease. Pathology findings, such as interstitial fibrosis, may provide insight into genetic etiology. The underutilization of services suggests a need for implementation strategies to improve uptake.

P-569 Reciprocal expanded carrier screening for intended parents and gamete donors: experience of a global surrogacy support network

Abstract Study question Is expanded carrier screening an effective tool to identify carriers of clinically relevant genes and determine the reproductive risk between a donor and recipient pair? Summary answer This study has determined that there is a strong rationale for performing matching according to expanded carrier screening results, especially for gamete donor programs. What is known already Carrier screening (CS) identifies carriers of autosomal recessive (AR) and/or X-linked (XL) genetic conditions to establish reproductive risk. If both partners (egg and sperm providers) carry a pathogenic variant in the same gene (co-carriage), there is 25% risk that offspring will be affected. The same risk is present for egg providers who carry an XL disorder. In expanded carrier screening (ECS), many clinically relevant conditions are screened simultaneously using a single-panel approach. The implementation of ECS is becoming commonplace across gamete donor banks. Providing recipients with a matching panel is key in determining reproductive risk and suitable treatment options. Study design, size, duration In this retrospective review, data was collected for 104 gamete recipients and 31 gamete donors who underwent ECS between March 2021-January 2024. ECS was provided through a single genetic testing laboratory, using a whole exome sequencing (WES) platform. The panel used for the gamete donors/recipients consisted of approximately 500 AR genes; optional analysis of 66 X-Linked genes was available for biologically female donors/recipients. Participants/materials, setting, methods In total, 104 gamete recipients were screened against one or more donor(s) using the same ECS panel. All donors/recipients underwent testing in a clinical setting and received pre/post-test genetic counselling, where required. The testing laboratory provided the referring clinician with the results for each individual. Matching was overseen by My Surrogacy Journey and the relevant donor bank. Donor-recipient match reports were requested from the testing laboratory. Individual and matched reports were used for this review. Main results and the role of chance In total, 76.9% (80/104) of gamete recipients presented with a positive result in at least one clinically relevant gene that could have an impact on reproductive planning. Between the 80 positive gamete recipients, 177 gene variants were carried; variant classification was available for 132 variants (74.6%). The majority of gene variants carried were classified as pathogenic (59.9%), meaning that these variants are associated with causing disease. Most frequently, recipients were carriers of a variant in 1-3 genes (1 gene: 36.3%; 2 genes: 27.5%; 3 genes: 22.5%). In addition to this, 77.4% (24/31) of gamete donors were identified to carry a variant in at least one clinically relevant gene, which includes one egg donor (3.2%; 1/24) who was a carrier of an XL condition. This meant that despite the lack of co-carriage in the AR gene(s) of interest, the recipient could not proceed with this donor due to the associated risk (25%). Of the 43 recipients matched with a donor, 9.3% (4/43) showed a high reproductive risk (25%) due to their reciprocal matching results. This expanded carrier screening strategy demonstrates significant utility in identifying positive carrier status and supporting donor-recipient matching programmes by determining high risk reproductive pairs. Limitations, reasons for caution This study was retrospective in nature. The majority of recipients were Caucasian (∼80% of cases). Ethnic groups are not homogenous; there can be significant genetic, cultural, and environmental diversity between/within ethnic groups. Decision outcome data should be collected to improve this work. Wider implications of the findings The findings from this analysis suggest that there is a strong rationale for performing donor-recipient matching using an ECS approach. Increasing awareness and accessibility of ECS in this setting should be a global initiative, with the ultimate aim of reducing the burden of genetic disease in donor-conceived offspring. Trial registration number N/A

Germline genome editing of human IVF embryos should not be subject to overly stringent restrictions

This paper critiques the restrictive criteria for germline genome editing recently proposed by Chin, Nguma, and Ahmad in this journal. While praising the authors for resisting fervent calls for an outright ban on clinical applications of the technology, this paper argues that their approach is nevertheless unduly restrictive, and may thus hinder technological progress. This response advocates for weighing potential benefits against risks without succumbing to excessive caution, proposing that ethical oversight combined with genetic scrutiny at the embryo stage post-editing can enable responsible use of the technology, ultimately reducing the burden of genetic diseases and enhancing human health, akin to how IVF transformed reproductive medicine despite strong initial opposition.

IMPACT OF CMA ON DIAGNOSIS AND CLINICAL MANAGEMENT OF NEONATES: A RETROSPECTIVE SINGLE CENTER STUDY OF A 10-YEAR COHORT

Abstract Introduction Congenital anomalies are one of the leading causes of mortality in neonatal period. The burden of genetic disease is high in neonates with congenital anomalies. Chromosomal microarray analysis (CMA) is the “first-tier” cytogenetic diagnostic test for individuals with multiple congenital anomalies. The aim of this study is to assess the diagnostic yield and clinical management impact of CMA in a large neonatal cohort over a 10-year period at a single medical center. Methods This is a retrospective study of a cohort of neonates tested by CMA at UVA Cytogenetics Laboratory between the years of 2013-2022. All individuals had either an isolated (major) congenital anomaly (CA) or multiple congenital malformations (MCA). We evaluated the diagnostic yield of the CMA in this neonate cohort and the frequency of positive CMA findings for specific phenotypes, as well as impact of CMA findings in the clinical management of patients. Results Of the 965 patients analyzed, 656 (68%) had normal results, 166 (17%) patients only had variants of uncertain significance (VUS), 128 (13%) patients had pathogenic alterations (thus confirmed genetic diagnosis), and 15 (2%) patients only had absence of heterozygosity (AOH) regions meeting our reporting criteria. Further details on presence of specific CNVs in the cohort and, positivity per presence/absence of multiple and specific anomalies is still ongoing and will be given in the presentation. For patients received a genetic diagnosis through CMA analysis, genetic findings were considered beneficial for clinical management, and a direct change to medical management occurred. Conclusion s: In this study, we found that the overall diagnostic yield for CMA in this neonate cohort is at approximately 13%. The confirmed genetic diagnosis affected the clinical management/treatment plan of this subset of neonatal patients. While first-tier testing for MCA and other indications is increasingly moving to ES/GS approaches, CMA continues to offer diagnostic and actionable genetic information in a timely matter. Overall, the implementation of CMA to a neonatal cohort at our center has increased the proportion of patients receiving a confirmed genetic diagnosis and affected the management/treatment plan of a subset of neonatal patients.

Nondisjunction in Trisomy 21: Origin and Mechanisms

Down’s Syndrome is a chromosomal abnormality with a gain of a third copy of chromosome 21, characterized by craniofacial abnormalities, intellectual developmental delay and growth retardation. In the present study, one-day-old neonate and a patient with an aborted fetus were presented to rule out genetic aberrations via CMA screening. DNA was extracted using from the case samples and evaluated by CMA Affymetrix platform. Chromosomal abnormalities in the fetus such as trisomy emerges due to several factors including maternal age, genetic mutational events, non-disjunction of chromosomes and epigenetic changes. Genetic Cause of trisomy 21 is chromosomal aneuploidy and gain of three copies of chromosome 21. The Trisomy 21 can occur due to Robertsonian translocation, Mosaicisms or duplication of critical region of chromosome 21. The trisomy 21 is the result of nondisjunction of homologous chromosomes 21 during gametogenesis at the time of embryo development. CMA is an effective molecular diagnostic tool for predicting and diagnosing chromosomal abnormalities which needs to be promoted in India for healthy pregnancy outcomes. We report two cases of confirmed post-natal Trisomy 21. The main aim of this study is to focus on genetic diagnosis and its awareness which is still lacking with 100% coverage, in developing countries to reduce the burden of genetic diseases and associated emotional and economic consequences.

Provision and availability of genomic medicine services in Level IV neonatal intensive care units

PurposeTo describe variation in genomic medicine services across level IV neonatal intensive care units (NICUs) in the United States and Canada. MethodsWe developed and distributed a novel survey to the 43 level IV NICUs belonging to the Children’s Hospitals Neonatal Consortium, requesting a single response per site from a clinician with knowledge of the provision of genomic medicine services. ResultsOverall response rate was 74% (32/43). Although chromosomal microarray and exome or genome sequencing (ES or GS) were universally available, access was restricted for 22% (7/32) and 81% (26/32) of centers, respectively. The most common restriction on ES or GS was requiring approval by a specialist (41%, 13/32). Rapid ES/GS was available in 69% of NICUs (22/32). Availability of same-day genetics consultative services was limited (41%, 13/32 sites), and pre- and post-test counseling practices varied widely. ConclusionWe observed large inter-center variation in genomic medicine services across level IV NICUs: most notably, access to rapid, comprehensive genetic testing in time frames relevant to critical care decision making was limited at many level IV Children’s Hospitals Neonatal Consortium NICUs despite a significant burden of genetic disease. Further efforts are needed to improve access to neonatal genomic medicine services.

Gene Therapy for Duchenne Muscular Dystrophy: Unlocking the Opportunities in Countries in the Middle East and Beyond.

Duchenne muscular dystrophy (DMD) is a severe neuromuscular disorder which leads to progressive muscle degeneration and weakness. Most patients die from cardiac or respiratory failure. Gene transfer therapy offers a promising approach to treating this disorder. Given the genetic disease burden, family size, and the high consanguinity rates in the Middle East, our objective is to address current practices and challenges of DMD patient care within two countries in this region, namely the United Arab Emirates and Kuwait, and to outline readiness for gene therapy. An expert panel meeting was held to discuss the DMD patient journey, disease awareness, current management of DMD, challenges faced and recommendations for improvement. Opportunities and challenges for gene therapy in both countries were also deliberated. A pre-meeting survey was conducted, and the results were used to guide the discussion during the meeting. DMD awareness is poor resulting in a delay in referral and diagnosis of patients. Awareness and education initiatives, along with an interconnected referral system could improve early diagnosis. Genetic testing is available in both countries although coverage varies. Corticosteroid therapy is the standard of care however there is often a delay in treatment initiation. Patients with DMD should be diagnosed and managed by a multi-disciplinary team in centers of excellence for neuromuscular disorders. Key success factors to support the introduction of gene therapy include education and training, timely and accessible genetic testing and resolution of reimbursement and cost issues. There are many challenges facing the management of DMD patients in the United Arab Emirates and Kuwait and most likely other countries within the Middle East. Successful introduction of gene therapy to treat DMD will require careful planning, education, capacity building and prioritization of core initiatives.

Health economic considerations of genetic disease screening - take Down syndrome as an example

The ongoing development of high-throughput sequencing technology and continuous decline of sequencing cost have made it possible to carry out large-scale screening for genetic diseases, which are the main component of birth defects. The screening of genetic diseases is expected to significantly reduce the rate of birth defects and the burden of genetic diseases to the affected families and the society. Taking Down syndrome as an example, through the analysis of the cost-benefit ratio of relevant screening programs, this article has summarized the socio-economic indicators to be considered during the design and development of genetic disease screening.

Spatio-temporal dynamics of pathogenic variants associated with monogenic disorders reconstructed with ancient DNA.

Genetic disease burden in ancient communities has barely been evaluated despite an ever expanding body of ancient genomes becoming available. In this study, we inspect 2729 publicly available ancient genomes (100 BP-52000 BP) for the presence of pathogenic variants in 32643 disease-associated loci. We base our subsequent analyses on 19 variants in seven genes-PAH, EDAR, F11, HBB, LRRK2, SLC12A6 and MAOA, associated with monogenic diseases and with well-established pathogenic impact in contemporary populations. We determine 230 homozygote genotypes of these variants in the screened 2729 ancient DNA samples. Eleven of these are in the PAH gene (126 ancient samples in total), a gene associated with the condition phenylketonuria in modern populations. The variants examined seem to show varying dynamics over the last 10000 years, some exhibiting a single upsurge in frequency and subsequently disappearing, while others maintain high frequency levels (compared to contemporary population frequencies) over long time periods. The geographic distribution and age of the ancient DNA samples with established pathogenic variants suggests multiple independent origin of these variants. Comparison of estimates of the geographic prevalence of these variants from ancient and contemporary data show discontinuity in their prevalence and supports their recurrent emergence. The oldest samples in which a variant is established might give an indication of their age and place origin, and an EDAR gene pathogenic variant was established in a sample estimated to be 33210-32480 calBCE. Knowledge about the historical prevalence of variants causing monogenic disorders provides insight on their emergence, dynamics and spread.

Familiarity, Knowledge, Attitude and Willingness towards Genetic Counselling among the South Indian Population

The effect of any kind of genetic disorder is almost irreversible in life, so it is very important to understand these disorders and the modern, effective preventive approaches available to reduce the familial and societal burden. This study aims to measure the awareness of Genetic Counselling (GC) and investigate personal factors like knowledge, attitude, and willingness towards the purpose of genetic counselling among the South Indian population. Individuals from the state of Tamil Nadu, Karnataka, Andhra Pradesh, Telangana, Kerala, and Pondicherry participated in the study. Knowledge score was generated for everyone, ranging from 19 to 42, with which varied results were generated compared to other variables. Four hundred and sixty-seven individuals completed the survey. About fifty-nine percent of the respondents reported familiarity with GC and the main source of knowledge was through media. Positive attitude and willingness towards GC were reported in the population. Knowledge of GC showed a different trend when compared to other studies of similar objectives. The need for more qualified professionals in the field and the inclusion of genetic counselling and testing as a primary preventive measure in government health care sectors will help reduce the burden of genetic diseases in families and society.

Patterns of occurrence and management abilities of birth defects: A study from a highly urbanized coastal district of India

BackgroundThe present study was aimed to find out the patterns of occurrence and management abilities of Birth Defects (BDs) in Visakhapatnam, one of the north coastal district of Andhra Pradesh, India during a span of five years. MethodsA cross-sectional investigation was held at District Early Intervention Center (DEIC), Visakhapatnam from 2016 to 2020. To identify the pattern and trend of different BDs including seasonal variations, a retrospective analysis of the health center's inpatient database for the past 5 years was done. Male and female children aged 2 months-18 years are included in the study with the prior permission of the concerned medical officer. The screening tool developed by the Ministry of Health and Family Welfare, India, was used for the study. ResultsAmong 26,423 cases, children with birth defects (BDs) are 962, 2229 with deficiencies, 7516 with diseases, and 15716 with Developmental Delays (DDs) & Disabilities were admitted during the study period. From birth defects, congenital deafness occurred in large numbers with 22.66%, and neural tube defect observed in a small number of cases with 0.83% during the period. From the side of deficiencies, severe acute malnutrition has mostly occurred (66.80%) and a small number of children were affected with goiter (1.70%). ConclusionThrough this study, it is observed that the incidence of birth defects, as well as genetic disease burden, is high in the Visakhapatnam district. Hence there is a need for strengthening of management services for these diseases in this region.

A brief summary of human molecular genetic techniques for clinical psychiatrists

Concerted and systematic efforts to understand genetics of human health and disease over the preceding 60 odd years have witnessed remarkable progress. The incremental gains through this journey were enabled by chromosomal analysis, recombinant deoxyribonucleic acid (DNA) techniques, notable discovery of single nucleotide polymorphisms following the Human Genome Project, consequent genome-wide variant-based studies, and now whole genome sequencing with ultimate diagnostic potential. Of note, success in prediction and prevention of chromosomal and single gene disorders comprising ~six to eight per cent each of all genetic disorders have been unprecedented but uncovering genetics of common complex disorders conferring ~60% of the genetic disease burden continues to pose a challenge and await new analytical paradigms - a mix of reductionist and organismal biology together with artificial intelligence and machine learning approaches being the current trend. A brief account of this path of progress in medical genetics and genomic insights along with limitations, to achieve the overarching goals of predictive, preventive, personalised, and participatory medicine is presented in this article.

Reproduction reimagined

Reproduction reimagined

Role of genomics literacy in reducing the burden of common genetic diseases in Africa.

BackgroundIn Africa, health practitioners and the current knowledge of the public on genetics and genomics is still very low and yet this has potential to reduce the burden of common genetic diseases. Many initiatives have promoted genomic research, infrastructure, and capacity building in Africa. What remains to be done is to improve genomics literacy among populations and communities while utilizing an array of strategies. Genomic literacy and awareness are key in the management of genetic diseases which includes diagnosis, prevention of complications and therapy. Africa is characterized by great cultural and language diversity thereby requiring a multidisciplinary approach to improving public and community genomics literacy and engagement. However, this is further complicated by having the fact that sub‐Saharan Africa is comprised of countries with the lowest literacy rates in the world.MethodsWe applied the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines to review genomic literacy in Africa using PubMed database.ResultsWe found very limited evidence of genomics literacy for genetic diseases in Africa.ConclusionWe propose a number of approaches that if adopted will significantly increase the genomic literacy and reduce the burden of genetic diseases in Africa.

Reducing the burden of genetic diseases via IVF and preimplantation genetic diagnosis

Reducing the burden of genetic diseases via IVF and preimplantation genetic diagnosis

Comparison of mid-age-onset and late-onset Huntington's disease in Finnish patients.

The phenotype of juvenile Huntington's disease (HD) differs clearly from that of adult-onset HD, but information about differences between mid-age-onset HD and late-onset HD (LOHD) is scarce. A national cohort of 206 patients with adult-onset HD was identified using national registries and patient records. LOHD was defined as age ≥60years at HD diagnosis. Genetic disease burden was assessed using CAG age product (CAP) score. LOHD comprised 25% of the adult-onset HD cohort giving a point prevalence of 2.38/100,000 in the Finnish population at least 60years of age. The proportion of LOHD out of new HD diagnoses increased from 21% in 1991-2000 to 33% in 2001-2010. At the time of diagnosis, patients with LOHD had 10.4 units (95% CI 4.8-15.9; p=0.0003) higher CAP scores, more severe motor impairment and slightly more severe functional impairment than that in patients with mid-age-onset HD. There was no difference in the rate of disease progression or survival between LOHD and mid-age-onset patients. The lifespans of deceased patients were shorter in mid-age-onset HD (p<0.001) and LOHD (p=0.002) than their life expectancies. Causes of death differed between the two patient groups (p=0.025). LOHD comprises a quarter of Finnish HD patients and the proportion appears to be increasing. Our results did not reveal differences in the phenotype between mid-age-onset HD and LOHD, but prospective studies are needed.

From sperm to offspring: Assessing the heritable genetic consequences of paternal smoking and potential public health impacts.

Individuals who smoke generally do so with the knowledge of potential consequences to their own health. What is rarely considered are the effects of smoking on their future children. The objective of this work was to review the scientific literature on the effects of paternal smoking on sperm and assess the consequences to offspring. A literature search identified over 200 studies with relevant data in humans and animal models. The available data were reviewed to assess the weight of evidence that tobacco smoke is a human germ cell mutagen and estimate effect sizes. These results were used to model the potential increase in genetic disease burden in offspring caused by paternal smoking, with specific focus on aneuploid syndromes and intellectual disability, and the socioeconomic impacts of such an effect. The review revealed strong evidence that tobacco smoking is associated with impaired male fertility, and increases in DNA damage, aneuploidies, and mutations in sperm. Studies support that these effects are heritable and adversely impact the offspring. Our model estimates that, with even a modest 25% increase in sperm mutation frequency caused by smoke-exposure, for each generation across the global population there will be millions of smoking-induced de novo mutations transmitted from fathers to offspring. Furthermore, paternal smoking is estimated to contribute to 1.3 million extra cases of aneuploid pregnancies per generation. Thus, the available evidence makes a compelling case that tobacco smoke is a human germ cell mutagen with serious public health and socio-economic implications. Increased public education should be encouraged to promote abstinence from smoking, well in advance of reproduction, to minimize the transmission of harmful mutations to the next-generation.

Pathogenic variants in the healthy elderly: unique ethical and practical challenges

Genetic research into ageing, longevity and late-onset disease is becoming increasingly common. Yet, there is a paucity of knowledge related to clinical actionability and the return of pathogenic variants to...

Pediatrics in 21st Century and Beyond.

Pediatrics is a dynamic discipline and there is awareness and hope for actualizing outstanding achievements in the field of child health in 21st century and beyond. Improved lifestyle and quality of children’s health is likely to reduce the burden of adult diseases and enhance longevity because seeds of most adult diseases are sown in childhood. Identification and decoding of human genome is expected to revolutionize the practice of pediatrics. The day is not far off when a patient will walk into doctor’s chamber with an electronic or digital health history on a CD or palmtop and a decoded genomic constitution. There will be reduced burden of genetic diseases because of selective abortions of “defective” fetuses and replacement of “bad” genes with “good” ones by genetic engineering. Availability of totipotent stem cells and developments in transplant technology are likely to revolutionize the management of a variety of hematologic cancers and life-threatening genetic disorders. The possibility of producing flawless designer babies by advances in assisted reproductive technologies (ARTs) is likely to be mired by several ethical and legal issues.The availability of newer vaccines by recombinant technology for emerging infective and for non-infective lifestyle diseases is likely to improve survival and quality of life. There is going to be a greater focus on the “patient” having the disease rather than “disease” per se by practicing holistic pediatrics by effective utilization of alternative or complementary strategies for health care. Due to advances in technology, pediatrics may get further dehumanized. A true healer cannot simply rely on technology; there must be a spiritual bond between the patient and the physician by exploiting the concept of psycho-neuro-immunology and body-mind interactions. In the years to come, physicians are likely to play “god” but medicine can’t achieve immortality because anything born must die in accordance with nature’s recycling blueprint. The medical science is likely to improve longevity but our goal should be to improve the quality of life.

Quantitative 7T phase imaging in premanifest Huntington disease.

In vivo MR imaging and postmortem neuropathologic studies have demonstrated elevated iron concentration and atrophy within the striatum of patients with Huntington disease, implicating neuronal loss and iron accumulation in the pathogenesis of this neurodegenerative disorder. We used 7T MR imaging to determine whether quantitative phase, a measurement that reflects both iron content and tissue microstructure, is altered in subjects with premanifest Huntington disease. Local field shift, calculated from 7T MR phase images, was quantified in 13 subjects with premanifest Huntington disease and 13 age- and sex-matched controls. All participants underwent 3T and 7T MR imaging, including volumetric T1 and 7T gradient recalled-echo sequences. Local field shift maps were created from 7T phase data and registered to caudate ROIs automatically parcellated from the 3T T1 images. Huntington disease-specific disease burden and neurocognitive and motor evaluations were also performed and compared with local field shift. Subjects with premanifest Huntington disease had smaller caudate volume and higher local field shift than controls. A significant correlation between these measurements was not detected, and prediction accuracy for disease state improved with inclusion of both variables. A positive correlation between local field shift and genetic disease burden was also found, and there was a trend toward significant correlations between local field shift and neurocognitive tests of working memory and executive function. Subjects with premanifest Huntington disease exhibit differences in 7T MR imaging phase within the caudate nuclei that correlate with genetic disease burden and trend with neurocognitive assessments. Ultra-high-field MR imaging of quantitative phase may be a useful approach for monitoring neurodegeneration in premanifest Huntington disease.