More than sample providers: how genetic researchers in Pakistan mobilized a prenatal diagnostic service for thalassemia

While unequally resourced partners from the so-called global South are often considered ‘mere sample providers’ in larger international genomics collaborations, in this paper, we show how they strategically work to mobilize their role in a global system of tissue exchange to deliver services for local communities. We unpack how a prenatal diagnostic service for thalassemia in Pakistan emerged out of the maneuvering efforts of internationally connected Pakistani researchers. By tracing the distributed capacities that emerged and circulated as they set about improving medical genetics in Pakistan, we outline some key conditions that led to the establishment of the service: first, the scale of unmet needs that geneticists faced when collecting data as part of their research that made medical genomics a relevant field; secondly, joint efforts between researchers and physicians that were engaged with the challenge of decreasing disease prevalence through diagnostics and abortion; and finally, the ways in which international research collaborations helped generate resources to improve medical genetics in Pakistan. To understand how genetic research and medicine is currently being developed in Pakistan, we need to ethnographically re-center our analyses in ways that allow us to identify the resourceful ways in which researchers maneuvre to secure locally relevant outcomes.

SOX10 Mutation Screening for 117 Patients with Kallmann Syndrome

Introduction Kallmann syndrome (KS) is a genetically heterogeneous condition characterized by hypogonadotropic hypogonadism (HH) and olfactory dysfunction. Although SOX10, a causative gene for Waardenburg syndrome (WS) and peripheral demyelinating neuropathy, central demyelination, WS, and Hirschsprung disease (PCWH), has previously been implicated in KS, the clinical significance of SOX10 variants as the cause of KS remains uncertain. Patients and Methods A total of 117 patients with KS underwent mutation screening of SOX10 and 14 other causative genes for KS/HH. Rare SOX10 variants were subjected to in silico and in vitro analyses. We also examined clinical data of the patients and their parents with SOX10 variants. Results Sequence analysis identified two heterozygous variants of SOX10 (c.1225G>T, p.Gly409* and c.475C>T, p.Arg159Trp) in patients 1–3, as well as in the parents of patients 1 and 3. The variants were assessed as pathogenic/likely_pathogenic, according to the American College of Medical Genomics guidelines. Both variants lacked in vitro transactivating activity for the MITF promoter and exerted no dominant-negative effects. Patients 1–3 carried no pathogenic variants in other genes examined. The patients presented with typical KS, while such features were absent in the parents of patients 1 and 3. None of the five variant-positive individuals exhibited hypopigmentation, while one and two individuals exhibited complete and partial hearing loss, respectively. Conclusion These results provide evidence that SOX10 haploinsufficiency accounts for a few percent of KS cases. SOX10 haploinsufficiency is likely to be associated with a broad phenotypic spectrum which includes KS without other clinical features of WS/PCWH.

The Implications of ncRNAs in the Development of Human Diseases

The mammalian genome comprehends a small minority of genes that encode for proteins (barely 2% of the total genome in humans) and an immense majority of genes that are transcribed into RNA but not encoded for proteins (ncRNAs). These non-coding genes are intimately related to the expression regulation of protein-coding genes. The ncRNAs subtypes differ in their size, so there are long non-coding genes (lncRNAs) and other smaller ones, like microRNAs (miRNAs) and piwi-interacting RNAs (piRNAs). Due to their important role in the maintenance of cellular functioning, any deregulation of the expression profiles of these ncRNAs can dissemble in the development of different types of diseases. Among them, we can highlight some of high incidence in the population, such as cancer, neurodegenerative, or cardiovascular disorders. In addition, thanks to the enormous advances in the field of medical genomics, these same ncRNAs are starting to be used as possible drugs, approved by the FDA, as an effective treatment for diseases.

Economic impact of medical genetic testing on clinical applications in Thailand

Background Although the clinical benefits of medical genetic testing have been proven, there has been limited evidence on its economic impact in Thai setting. Thus, this study aimed to evaluate the economic impact of genetic testing services provided by the Center for Medical Genomics (CMG) in Thailand. Methods Cost-benefit analysis was conducted from provider and societal perspectives. Cost and output data of genetic testing services provided by the CMG during 2014 to 2018 and published literature reviews were applied to estimate the costs and benefits. Monetary benefits related to genetic testing services were derived through human capital approach. Results The total operation cost was 126 million baht over five years with an average annual cost of 21 million baht per year. The net benefit, benefit-to-cost ratio, and return on investment were 5,477 million baht, 43 times, and 42 times, respectively. Productivity gain was the highest proportion (50.57%) of the total benefit. Conclusions The provision of genetic testing services at the CMG gained much more benefits than the cost. This study highlighted a good value for money in the establishment of medical genomics settings in Thailand and other developing countries.

The International Conference on Intelligent Biology and Medicine (ICIBM) 2020: Data-driven analytics in biomedical genomics

This editorial summarizes eight research articles included in this supplement issue for the 2020 International Conference on Intelligent Biology and Medicine (ICIBM 2020) conference, that was held on August 9-10, 2020 (virtual conference), with a topic on data-driven analytics in biomedical genomics. These articles cover a wide range of topics in medical genomics that focus on integrative analysis of genomics data together with other types of data toward understanding complex human diseases, including cancer. With the growing importance of data analytics in biomedical science, we expect this collection of research articles provides scientific discussions in this direction.

Expanded carrier screening for monogenic diseases for Australians of Aboriginal and/or Torres Strait Islander descent

Accounting for ancestral diversity is essential in medical genomics. For this reason, inclusion of Indigenous and other under-represented populations in genomic research is necessary to ensure equitable outcomes and access to precision medicine and disease prevention. Here we discuss this issue in the context of a national program of pre-conception expanded carrier screening (ECS) for recessive monogenic diseases, funded by the Australian Government as part of its Genomics Health Futures Mission. Current knowledge and research about monogenic diseases are mainly based on people with European ancestry and little is known about pathogenic DNA variants in people of Aboriginal and/or Torres Strait Islander descent. We argue that significant effort is required to build the evidence base and genomic reference data required before ECS can bring significant clinical benefit for many Aboriginal and/or Torres Strait Islander Australians. Research programs and creation of reference data are required to correct this bias. They are essential steps to achieving the Australian Government’s objectives and its commitment “to leveraging the benefits of genomics in the health system for all Australians”. They require culturally safe, community-led research and community engagement embedded within national health and medical genomics programs that ensure that new knowledge is integrated into medicine and health services in ways that address the cultural and health needs of Indigenous people. Until this occurs, Australians of European ancestry stand to benefit most and, as a consequence, Indigenous Australians and other minority groups in the Australian population are at risk of being, in relative terms, further disadvantaged.

Bioinformatics Methods in Medical Genetics and Genomics

Medical genomics relies on next-gen sequencing methods to decipher underlying molecular mechanisms of gene expression. This special issue collects materials originally presented at the “Centenary of Human Population Genetics” Conference-2019, in Moscow. Here we present some recent developments in computational methods tested on actual medical genetics problems dissected through genomics, transcriptomics and proteomics data analysis, gene networks, protein–protein interactions and biomedical literature mining. We have selected materials based on systems biology approaches, database mining. These methods and algorithms were discussed at the Digital Medical Forum-2019, organized by I.M. Sechenov First Moscow State Medical University presenting bioinformatics approaches for the drug targets discovery in cancer, its computational support, and digitalization of medical research, as well as at “Systems Biology and Bioinformatics”-2019 (SBB-2019) Young Scientists School in Novosibirsk, Russia. Selected recent advancements discussed at these events in the medical genomics and genetics areas are based on novel bioinformatics tools.

The role of globotriaosylsphingosine in the diagnosis of Fabry disease in Russian patients

Болезнь Фабри (БФ), MIM 301500 - Х-сцепленное заболевание, обусловленное мутациями в гене GLA, который кодирует фермент α-галактозидазу А (α-гал А). В 2017 году в лаборатории молекулярной генетики и медицинской геномики «НМИЦ здоровья детей» Министерства Здравоохранения России был разработан и внедрен метод определения концентрации лизо-Гб3 для диагностики БФ. К настоящему времени нами исследовано 9830 образцов сухих пятен крови из различных регионов России, полученных от 8832 пациентов мужского пола и 998 женского пола, в возрасте от 12 до 70 лет. В результате проведенного исследования у 33 мужчин было выявлено снижение активности фермента, а у 31 из них - повышение концентрации лизо-Гб3, у этих мужчин были обнаружены патогенные варианты гена GLA, тогда как у двух оставшихся мужчин были найдены полиморфные варианты гена GLA, описанные ранее как аллели, обладающие псевдодефицитной активностью. Кроме того, были выявлены 2 женщины с повышенной концентрацией лизо-Гб3, у которых также были обнаружены патогенные варианты гена GLA, тогда как у 5 женщин с псевдодефицитными аллелями гена GLA концентрация лизо-Гб3 была в норме. Наше исследование продемонстрировало преимущество измерения концентрации биомаркера лизо-Гб3 по сравнению с определением активности фермента α-гал А для первичной диагностики мужчин с подозрением на БФ, a также возможность использования этого биомаркера для первичной диагностики женщин с подозрением на БФ. Fabry Disease (BF), MIM 301500 - X-linked disease caused by mutations in the GLA gene, which encodes the enzyme α-galactosidase A (α-gal A). In 2017, a method for determining the concentration of lyso-Gb3 for the diagnosis of FD was developed and introduced in the laboratory of molecular genetics and medical genomics of the “National Medical Research of Children’s Health Federal State Autonomous Institution of the Ministry of Health of the Russian Federation. To date, we have studied 9830 samples of dry blood spots from various regions of Russia, obtained from 8832 male and 998 female patients, aged 12 to 70 years. As a result of the study, a decrease in enzyme activity was detected in 33 men, and in 31 of them an increase in the concentration of lyso-Gb3, pathogenic variants of the GLA gene were found in these men, while the two remaining men found polymorphic variants of the GLA gene, previously described as alleles with pseudodeficiency activity. In addition, 2 women with an increased concentration of lyso-Gb3 were identified, in whom pathogenic variants of the GLA gene were also detected, while in 5 women with pseudo-deficient alleles of the GLA gene, the concentration of lyso-Gb3 was normal. Our study demonstrated the advantage of measuring the concentration of the lyso-Gb3 biomarker compared to determining the activity of the α-gal A enzyme for the initial diagnosis of men with suspected FD, as well as the possibility of using this biomarker for the initial diagnosis of women with suspected DF.