Deciphering the mutation spectrum in south Indian children with congenital anomalies of the kidney and urinary tract

Background Congenital anomalies of the kidney and urinary tract (CAKUT) cover a spectrum of structural malformations that result from aberrant morphogenesis of kidney and urinary tract. It is the most prevalent cause of kidney failure in children. Hence, it is important from a clinical perspective to unravel the molecular etiology of kidney and urinary tract malformations. Causal variants in genes that direct various stages of development of kidney and urinary tract in fetal life have been identified in 5–20% of CAKUT patients from Western countries. Recent advances in next generation sequencing technology and decreasing cost offer the opportunity to characterize the genetic profile of CAKUT in Indian population and facilitate integration of genetic diagnostics in care of children with CAKUT. Methods Customized targeted panel sequencing was performed to identify pathogenic variants in 31 genes known to cause human CAKUT in 69 south Indian children with CAKUT. The NGS data was filtered using standardized pipeline and the variants were classified using ACMG criteria. Genotype and phenotype correlations were performed. Results The cohort consisted of children mostly with posterior urethral valve (PUV) (39.1%), vesico-ureteric reflux (VUR) (33.3%) and multi-cystic dysplastic kidney (MCDK) (7.2%). No pathogenic or likely pathogenic variants were identified in the study. Most of our variants (n = 39, 60%) were variants of unknown significance with 25.6% (10/39) of them were identified as potentially damaging but were novel variants. Conclusions The present study did not identify any disease-causing monogenic variants in the cohort. The absence of genetic cause may be due to limitations of panel-based testing and also due to higher proportion of children with abnormalities in lower urinary tract than hypodysplasia of kidneys. Clinical, larger targeted panel or whole exome sequencing may be a better method to characterize the genetic profile of Indians patients with CAKUT.

BIOLOGICAL SESSION“THE IMPORTANCE OF G. GAMOW'S IDEAS FOR BIOLOGY OF THE 21st CENTURY” AT THE XXI GAMOW INTERNATIONAL ASTRONOMICAL CONFERENCE-SCHOOL IN ODESSA (15-21 AUGUST, 2021)

Третій рік поспіль в межах Гамовської конференції працює Біологічна секція: «Важливість ідей Г.А. Гамова для біології 21-ого століття», організація якої викликана великою повагою до особистості вченого Георгія Антоновича Гамова, наукові інтереси якого об’єднали астрофізику, космологію та молекулярну біологію. Цього року Біологічна секція працювала в режимі on-line 17.08.2021. Роботу секції розпочали з виступу професора Тобіуса Дельбрюка (Institute of Neuroinformatics – ETH and University of Zurich, Zurich, Switzerland), сина видатного фізика, Нобелевського лауреата Макса Дельбрюка (в певний період товариша Г.А. Гамова). Професор Тобіус Дельбрюк назвав свою доповідь – "Out of this world: Recounting Max's Delbruck memories of George Gamow”. Ця доповідь, присвячена феноменальній особистості Г.А. Гамова, придала засіданню біологічної секції емоційну атмосферу наближення до великих ідей, що надали і зараз надають поштовх для розвитку молекулярної біології. Значну зацікавленість учасників секції викликала доповідь Dr. V.N. Korzun (KWS SAAT SE & Co. KGaA (м. Айнбек, Німеччина) «Applications of genetic and genomic research in cereals», що продемонструвала впровадження в селекційний процес сучасних молекулярно-генетичних технологій. З доповіддю «DNA-protein interactions as a tool of synthetic biology», що присвячена високо технологічним розробкам зі створення біосенсорів науково-виробничою фіромою Explogen LLC (EXG) (м. Львів, Україна) виступив к.б.н. Ю. Ребець. Наступна пленарна доповідь «Using the G.A. Gamow’s ideas for molecular genetic diagnostics of infectious and somatic human diseases at the current stage of medical development» була представлена білоруськими вченими, а саме професор С.А. Касцьюк розповіла про молекулярно-генетичні дослідження, що виконуються в Білоруській медичній академії післядипломної освіти. Dr. Yu. Monchak з McGill University (м. Монреаль, Канада) також представив доповідь присвячену впровадженню ДНК-технологій в діагностику патології людини ˗ «Targeted therapy, DNA sequence and the race against neoplasia». Ця доповідь викликала велику зацікавленість учасників біологічної секції. Молоді науковці Іщенко О.О., Жарікова Д.О., Роман І.І., Доля Б., Рошка Н.М., Чубик І.Ю., Попович Ю.А., Топораш М.К., Пидюра М.О. – доктори філософії з біології, кандидати наук, аспіранти, що займаються дослідженнями в галузі молекулярної біології представили дев’ять доповідей, що відбивають результати виконаних досліджень у низці провідних університетів нашої країни, а саме у Львівському національному університеті ім. І. Франка, у Одеському національному університеті імені І.І. Мечникова, у Чернівецькому національному університеті ім. Юрія Федьковича та ДУ «Інституті харчової біотехнології та Геноміки» (м. Київ). Представлені доповіді викликали жвавий інтерес, а формат on-line дозволів об’єднати у роботі секції понад 35 учасників з різних країн ˗ України, Білорусі, Швейцарії, Німеччини, Канади і Казахстану.

Preimplantation and prenatal genetic diagnostics in Russian Federation: ethical and legal issues

The topicality of the article is due to the strategy of transition to personalized medicine in Russia, based, among other things, on technologies of preimplantation and prenatal genetic diagnostics. The purpose of the article is to analyze the main directions of ethical and legal support for the development of these technologies. The work is based on the study of relevant international regulations, foreign and Russian legislation using the methods of legal-dogmatic and philosophical-legal analysis. The article substantiates the need for a clearer distinction between legal and moral-religious approaches to regulating relations in applying these technologies. The task is to find legal structures that can take into account the moral aspects of the problem without replacing legal regulation with an appeal to moral and religious values and norms. An example of this approach is the development of a legal regime for manipulations with embryo in vitro, in which the necessary legal protection of the embryo is provided by recognizing its special ontological status as a constitutional value of the common good. From these positions, the author identifies a range of issues that should form the organizational and legal context necessary to ensure adequate guarantees of human rights in the field of application of the considered genetic technologies. The legal regulation of this range of issues should be fixed in a special federal law on genetic testing.

Optical Genome Mapping in Routine Human Genetic Diagnostics—Its Advantages and Limitations

In recent years, optical genome mapping (OGM) has developed into a highly promising method of detecting large-scale structural variants in human genomes. It is capable of detecting structural variants considered difficult to detect by other current methods. Hence, it promises to be feasible as a first-line diagnostic tool, permitting insight into a new realm of previously unknown variants. However, due to its novelty, little experience with OGM is available to infer best practices for its application or to clarify which features cannot be detected. In this study, we used the Saphyr system (Bionano Genomics, San Diego, CA, USA), to explore its capabilities in human genetic diagnostics. To this end, we tested 14 DNA samples to confirm a total of 14 different structural or numerical chromosomal variants originally detected by other means, namely, deletions, duplications, inversions, trisomies, and a translocation. Overall, 12 variants could be confirmed; one deletion and one inversion could not. The prerequisites for detection of similar variants were explored by reviewing the OGM data of 54 samples analyzed in our laboratory. Limitations, some owing to the novelty of the method and some inherent to it, were described. Finally, we tested the successful application of OGM in routine diagnostics and described some of the challenges that merit consideration when utilizing OGM as a diagnostic tool.

Genetic testing and diagnosis of inherited retinal diseases

Inherited retinal diseases (IRDs) are a diverse group of degenerative diseases of the retina that can lead to significant reduction in vision and blindness. Because of the considerable phenotypic overlap among IRDs, genetic testing is a critical step in obtaining a definitive diagnosis for affected individuals and enabling access to emerging gene therapy–based treatments and ongoing clinical studies. While advances in molecular diagnostic technologies have significantly improved the understanding of IRDs and identification of disease-causing variants, training in genetic diagnostics among ophthalmologists is limited. In this review, we will provide ophthalmologists with an overview of genetic testing for IRDs, including the types of available testing, variant interpretation, and genetic counseling. Additionally, we will discuss the clinical applications of genetic testing in the molecular diagnosis of IRDs through case studies.

Genetic Diagnostic Strategies and Counseling for Families Affected by Congenital Diaphragmatic Hernia

Congenital diaphragmatic hernia (CDH) is a relatively common and severe birth defect with variable clinical outcome and associated malformations in up to 60% of patients. Mortality and morbidity remain high despite advances in pre-, intra-, and postnatal management. We review the current literature and give an overview about the genetics of CDH to provide guidelines for clinicians with respect to genetic diagnostics and counseling for families. Until recently, the common practice was (molecular) karyotyping or chromosome microarray if the CDH diagnosis is made prenatally with a 10% diagnostic yield. Undiagnosed patients can be reflexed to trio exome/genome sequencing with an additional diagnostic yield of 10 to 20%. Even with a genetic diagnosis, there can be a range of clinical outcomes. All families with a child with CDH with or without additional malformations should be offered genetic counseling and testing in a family-based trio approach.

PROBLEMS OF AGE AND GENETIC DIAGNOSTICS OF QUATERNARY DEPOSITS IN THE VALLEY OF THE YENISEI RIVER MIDDLE COURSE (YENISEI – LOWER ANGARA STRATIGRAPHIC REGION AND THE MINUSINSK BASINS AREA)

The article is devoted to the state of stratigraphic exploration maturity of the Eopleistocene – Neo-Рleistocene Quaternary deposits on the boundary of mountain and plain territories in the non-glacial area. The material analysis shows an inadequate rationale of the existing stratigraphic schemes, according to which the ladder of alluvial terraces of these territories was formed sequentially during the Eopleistocene, Neo-Pleistocene and Holocene. The revising of representative sections was carried out, the provision of them with geochronological data, the accuracy of age and genetic diagnostics were evaluated.

An Integrated clinical pathway for diagnosis, treatment and care of rare diseases: model, operating procedures, and results of the project TRANSLATE-NAMSE funded by the German Federal Joint Committee

Background Diagnosis, treatment, and care of patients with rare diseases require multidisciplinary cooperation between medical and paramedical specialities and with patients and families. Innovative genetic diagnostics, whole exome and whole genome sequencing (WES, WGS) has enlarged the diagnostic toolkit but also increased the complexity of the endeavour. Structured multidisciplinary clinical pathways (CPW) can guide diagnosis, treatment, and care of patients with rare diseases, link scientific evidence to clinical practice and optimise clinical outcomes whilst maximising clinical efficiency. Results In contrast to the common approach of appending disease-specific CPWs to disease-specific guidelines, we suggest a generic CPW manoeuvring the patient along the way of finding the correct diagnosis by applying the best diagnostic strategy into an appropriate system of treatment and care. Available guidelines can be integrated into the generic CPW in the course of its application. The approach also applies to situations where a diagnosis remains unsolved. The backbone of the generic CPW is a set of multidisciplinary structured case conferences projecting and evaluating diagnostic and/or therapeutic steps, enforcing to integrate best scientific evidence with clinical experience. The generic CPW is stated as a flowchart and a checklist which can be used to record and document parsimoniously the structure, process and results of a patient’s pathway, but also as a data model for research. It was applied in a multicentre setting with 587 cases each with a presumptive diagnosis of a rare disease. In 369 cases (62.8%) a diagnosis could be confirmed, and multidisciplinary treatment and/or care was initiated. The median process time from first contact until confirmation of diagnosis by WES was 109 days and much shorter than diagnostic delays reported in the literature. Application of the CPW is illustrated by two case reports. Conclusions Our model is a tool to change the diagnostic odyssey into an organised and trackable route. It can also be used to inform patients and families about the stages of their individual route, to update health care providers only partially involved or attending specialised treatment and care, like the patient’s or family’s primary physician, and finally to train novices in the field.