Genetic forms of developmental delay and intellectual disability in the practice of the medical genetic consultation of Research Centre for Medical Genetics

Задержка психического развития (ЗПР) и умственная отсталость (УО) являются частыми причинами направления пациентов на медико-генетическое консультирование. Наблюдаемый в последние годы значительный рост числа нозологических форм моногенных и хромосомных болезней среди пациентов с ЗПР или УО медико-генетической консультации Медико-генетического научного центра отражает повышение эффективности диагностики наследственных форм данной патологии. Цели исследования: оценка долей клинически и/или лабораторно подтвержденных хромосомных, моногенных заболеваний и болезней геномного импринтинга, диагностированных у пациентов с ЗПР или УО; определение эффективности разных методов диагностики генетических форм ЗПР и УО; расчет сегрегационной частоты для оценки вклада моногенных форм с аутосомно-рецессивным и X-сцепленным рецессивным типами наследования в недифференцированные ЗПР и УО. Выборка включала 2350 пациентов с ЗПР или УО различных степеней тяжести и пациентов с диагнозом, предполагающим развитие ЗПР или УО по мере взросления, проконсультированных врачами-генетиками консультативного и научно-консультативного отделов Медико-генетического научного центра им. Бочкова в 2006, 2007, 2016 гг. и первой половине 2017 г. В исследуемый период (2006, 2007, 2016 и первая половина 2017 г.) отмечается тенденция к снижению доли хромосомной патологии среди всех пациентов выборки. В группе пациентов с ЗПР или УО с аномалиями хромосом с течением времени отмечается значительный рост доли структурной хромосомной патологии и снижение доли заболеваний, обусловленных изменением числа хромосом. Доля моногенных форм остается практически неизменной в исследуемый период. Внутри данной группы отмечается некоторый рост доли аутосомно-доминантной патологии. Доля пациентов с ЗПР или УО, обусловленных болезнями геномного импринтинга, достоверно различается в исследуемые годы, со временем отмечается тенденция к ее уменьшению. Доля только клинически установленных синдромов без лабораторного подтверждения значительно снижается в исследуемый период. Максимальная диагностическая эффективность среди лабораторных генетических методов показана для микросателлитного анализа, MLPA, хромосомного микроматричного анализа и секвенирования нового поколения. Developmental delay (DD) and intellectual disability (ID) are frequent reasons for referring patients for medical genetic counseling. A significant increase in the number of nosological forms of monogenic and chromosomal diseases among patients with DD or ID in medical genetic consultation of Bochkov Research Centre for Medical Genetics in recent years reflects an increase in its effectiveness in diagnosing this pathology. Purpose of the research: 1. To estimate the proportion of clinically and/or laboratory-confirmed chromosomal, monogenic, and genomic imprinting disorders diagnosed in patients with DD or ID consulted by geneticists from the consultation and scientific consulting departments of the Bochkov Research Centre for Medical Genetics in 2006, 2007, 2016, and the first half of 2017. 2. Determination of the effectiveness of different diagnostic methods of genetic forms DD and ID. 3. Calculation of segregation frequency to estimate the contribution of monogenic forms with autosomal recessive and X-linked recessive types of inheritance among undifferentiated cases of DD and ID. The sampling for the analysis included 2350 patients with DD or ID of varying severity, as well as patients with a diagnosis suggesting the development of DD or ID as they mature, consulted by geneticists from the consultation and scientific consulting departments of the Bochkov Research Centre for Medical Genetics in 2006, 2007, 2016, and the first half of 2017. During the research period (2006, 2007, 2016, and the first half of 2017), there was a decreasing trend in the proportion of chromosomal pathology among all patients of the sampling. Within the group of patients with DD or ID with chromosomal pathology, a significant increase in the proportion of structural chromosomal pathology and a decrease in the proportion of diseases caused by changes in the number of chromosomes is noted over time. The proportion of monogenic forms remains practically unchanged during the study period. Within this group, there is some increase in the share of AD pathology. The proportion of patients with DD or ID caused by genomic imprinting disorders varies significantly in the years studied, with a tendency to decrease over time. The proportion of only clinically identified syndromes without laboratory confirmation decreases significantly during the study period. The maximum diagnostic efficiency among laboratory genetic methods has been shown for microsatellite analysis, MLPA, chromosomal microarray analysis (CMA) and next generation sequencing (NGS).

Prevention and diagnosis of congenital malformations

The problem of inherited pathology remains relevant, gaining in recent decades and medical and biological and acute socio-economic importance. Purpose. To analyse statistical data on prevention and diagnosis of congenital malformations in Primorsky Krai. Material and methods. As a material of the study, the data of medical-genetic consultation and medical-genetic assistance were used. Information Federal State Statistics Service for the Primorsky Territory on the birth rate. The data were processed using descriptive statistics. Results. According to the study, during 2015-2017, within the framework of the budget 5561 (2015), 5537 (2016), and 5418 (2018), patients visited reception for the medical and genetic consultation and received the corresponding assistance. Most congenital malformation of compulsory registration was recorded in large urban districts (34.1-5.7%), and the remaining municipalities accounted for 0.2-3%. Diseases of the circulatory system, deformations of the musculoskeletal system, diseases of the urogenital system (frequency of occurrence 36.5%, 13.8%, 11.3%, respectively) dominated the structure of congenital malformations. The most common congenital malformations of mandatory registration identified during the prenatal screening - hypospadias and Down syndrome were identified. The most common congenital malformations identified during mass neonatal screening included hypothyroidism, phenylketonuria, cystic fibrosis. Conclusion. Possible reasons for the high level of congenital malformations in some areas of Primorsky Krai are lack of public awareness of the problem, environmental conditions, distance from the regional medical and genetic centre, lack of qualified specialists and modern equipment for research in municipal hospitals. However, proper medical and genetic counselling, prenatal diagnosis and monitoring play a critical role in the prevention of congenital malformations.

Awareness and perception of medical genetic services among Malaysian parents of autism spectrum disorders children: the lessons to be learned

Purpose Autism spectrum disorder (ASD) is a group of complex neurodevelopmental disorders with uncertain etiology. Evidence shows that genetic testing can explain about 20% of cases. This study aims to assess the level of awareness and perception of medical genetic services among Malaysian parents with ASD children. Design/methodology/approach A cross-sectional survey using an interviewer-administered questionnaire was done among 111 parents of children with ASD from August 2017 to September 2019 in two clinics in Malaysia. Findings A majority of children with ASD (80.20%) were male and diagnosed at the age of 3–4 years old (47.80%). When the autistic child was born, most mothers and fathers were aged 26–30 (40.50%) and 31–35 years old (42.30%), respectively. Another child with ASD in nuclear and extended families was reported for 11.70% and 13.50%, respectively. Only 24.30% have seen a professional genetic consultant, and 19.8% have done genetic testing for affected children. The mean score of awareness of genetic services for ASD was 2.48 ± 3.30. Having medical insurance and another child with ASD in the nuclear family was significantly associated with a higher level of awareness (p = 0.01 and p < 0.001, respectively). Most of the participants have a positive perception of these services. Originality/value Regardless of demographic factors, participants have poor awareness of genetic services for ASD, likely because the primary physician did not recommend it upon diagnosis. Increasing health-care providers’ knowledge about the current potential of genetic testing for ASD and educational campaigns for the public are critical components of using available genetic tests to improve ASD management.

THE WOUNDED SELF AND THE DISMEMBERED FLESH: ANTHROPOLOGICAL SENSE OF COMMUNICATION DYSFUNCTIONS

В статье анализируются коммуникативные дисфункции между пациентами, генетиками-консультантами и врачами в практиках медико-генетического консультирования. Несмотря на очевидную полезность генетических рекомендаций для консультируемого и членов его семьи, а также факт оплаты им услуги консультирования, он (консультируемый) этим рекомендациям часто не следует, подвергая и свою жизнь, и жизнь близких опасности. Как понять эту странность? В качестве виртуального участия в гибридном форуме, обсуждаются два казуса из практики генетического консультирования, которые, при существенном сходстве ситуации, отличаются друг от друга наличием или отсутствие доверия пациентов к научному знанию и экспертным суждениям генетика консультанта. В целях теоретического истолкования поставленной проблемы вводится предположение о самости как коммуникативной дисфункции, которая диагностируется в различных ценностных координатах либо как некомплаентность (noncomplience) в директивных моделях консультирования, либо как отказ от сотрудничества (nonadherence) в недирективных. Если же учесть, что в основе медицины как культурной практики лежит чувство солидарности перед лицом телесного страдания, то в этом плане странное, контрпродуктивное поведение пациента может указывать на наличие глубоких проблем в основах современной социальности. Предлагается формулировка нарративного императива. The article analyzes communication dysfunctions between patients, consulting geneticists and doctors in the practice of medical genetic counseling. Despite the obvious usefulness of genetic advice for the counseled and their family members, as well as the fact that patients pay for counseling services, they (the counseled) often do not follow these recommendations, putting both their own lives and the lives of the loved ones at risk. How to understand this oddity? As a virtual participation in a hybrid forum, two cases from the practice of genetic counseling are discussed, which, with a significant similarity of the situation, differ from each other in the presence or absence of patient confidence in the scientific knowledge and expert judgments of the geneticist. In order to theoretically interpret the problem posed, an assumption is introduced about the self as a communication dysfunction, which is diagnosed in various value coordinates either as noncompliance in directive models of counseling, or as nonadherence in non-directive ones. If we consider that medicine as a cultural practice is based on a sense of solidarity in the face of bodily suffering, then, in this regard, the patient’s strange, counterproductive behavior may indicate the presence of deep problems in the foundations of modern sociality. The formulation of the narrative imperative is proposed.

Analysis of the structure of developmental delay and intellectual disability among patients of the Research Centre for Medical Genetics

Задержка психического развития (ЗПР) и умственная отсталость (УО) являются частыми симптомами у пациентов, консультируемых врачом-генетиком. Цель исследования: оценка структуры и разнообразия нозологических форм ЗПР и УО и их динамики среди пациентов, проконсультированных в ФГБНУ МГНЦ. Работа выполнена на материале, извлеченном из медико-генетических карт пациентов, проконсультированных врачами-генетиками консультативного и научно-консультативного отделов в 2006 и 2007 годах и через 10 лет -в 2016 и 2017 годах. Общее число обработанных медико-генетических карт за 4 анализируемых года составило 14301 по всем нозологиям, общее число карт пациентов с ЗПР или УО за 4 года составило 2321 карту. Общее количество пациентов с ЗПР или УО за 4 года составило 2350, при этом доли пациентов с ЗПР или УО, проконсультированных в 2016-2017 годах, достоверно увеличились по сравнению с долями таких пациентов, проконсультированных в 2006-2007 годах. В исследуемые периоды структура ЗПР и УО осталась практически неизменной по таким критериям, как пол и возраст. Доли пациентов с ЗПР и УО, обусловленными факторами окружающей среды и генетическими причинами, также не претерпели изменений. Наблюдается значительное увеличение числа пациентов с ЗПР или УО в 2016 и 2017 гг. с диагнозом, подтвержденным биохимическими, молекулярно-генетическими или цитогенетическими методами. Количество нозологических форм ЗПР и УО, подтвержденных молекулярно-генетическими или цитогенетическими методами, возросло почти в 5 раз за исследуемый десятилетний период. Существенное увеличение числа пациентов с лабораторно верифицированными генетическими формами ЗПР или УО в 2016 и 2017 годах обусловлено значительным прогрессом в области ДНК-диагностики синдромов, включающих ЗПР и УО, а также появлением новых методов исследований: хромосомного микроматричного анализа и секвенирования нового поколения. Background: Developmental delay (DD) and intellectual disability (ID) are frequent symptoms in patients consulted by a geneticist. Purpose of the research: evaluation of the structure and variety of nosological forms of DD and ID and their dynamics among patients consulted by geneticists of the counseling unit and research and counseling department of the Research Centre for Medical Genetics in 2006, 2007, 2016 and 2017. Materials and methods: The present work was performed on the material taken from the medical genetic cards of patients of the Research Centre for Medical Genetics consulted by geneticists of the counseling unit and research and counseling department in 2006 and 2007 and 10 years later in 2016 and 2017. The total number of medical genetic cards processed during the 4 analyzed years was 14301 for all nosologies; the total number of cards of patients with DD or ID during the 4 years was 2321 cards. The total number of patients with DD or ID over the 4 analyzed years was 2350. Meanwhile the proportions of patients with DD or ID consulted in 2016-2017 increased significantly compared to the proportions of such patients consulted in 2006-2007. Results: During the research period (2006, 2007, 2016, and 2017) the structure of DD and ID remained almost unchanged for criteria such as gender and age. The proportions of patients with DD or ID caused by environmental factors and genetic causes also did not change. There was a significant increase in the number of patients with DD or ID in 2016 and 2017 with a diagnosis confirmed by biochemical, molecular genetic or cytogenetic methods. The number of nosological forms of PD and OA confirmed by molecular genetic or cytogenetic methods increased almost 5-fold over the ten-year period research. Conclusions: The significant increase in the number of patients with laboratory verified genetic forms of DD or ID in 2016 and 2017 is explained by significant advances in DNA diagnostics of syndromes manifesting in DD or ID, as well as the appearance of new research methods - chromosome microarray analysis and next-generation sequencing.

Somatic mosaicism in sporadic retinoblastoma

Введение. Спорадическая ретинобластома развивается в результате мутаций de novo в обоих аллелях гена RB1 в клетках сетчатки глаза. При спорадической ретинобластоме первоначальная мутация в гене RB1 нередко является мозаичной, то есть образуется в постзиготической ранней эмбриональной клетке, что приводит к неравномерному распределению мутантных клонов между различными тканями организма. Возможность идентифицировать мозаичный вариант мутации в гене RB1 имеет значение как для медико-генетического консультирования, так и для клинического ведения пациентов, поскольку мозаицизм влияет на развитие клинической картины заболевания, риск развития опухоли в другом глазу и других опухолей и на риск передачи мутации следующему поколению. Цель: установить частоту и спектр постзиготических мозаичных мутаций в гене RB1 в выборке больных со спорадической ретинобластомой, определить содержание мутантного аллеля в образцах с мозаицизмом. Метод. Исследование проведено на материале ДНК лимфоцитов крови больных со спорадической ретинобластомой. Скрининг точковых мутаций, малых инсерций/делеций в гене RВ1 осуществляли методом полупроводникового высокопроизводительного параллельного секвенирования (ВПС). Исключение протяженных делеций в гене RВ1 проводили методом MLPA. Для поиска мозаичных мутаций с очень низким содержанием (менее 10%) мутантного аллеля был разработан и проведен углубленный анализ данных ВПС, основанный на биоинформатических и статистических подходах. Для верификации выявленных мозаичных патогенных мутаций использовали секвенирование ДНК по Сэнгеру. Результаты. В исследованной выборке больных со спорадической унилатеральной формой ретинобластомы мозаичные мутации встречаются чаще, чем при спорадической билатеральной форме; различия статистически достоверны. В то же время, частоты мозаичных мутаций с высокой и низкой представленностью мутантных аллелей между группами больных с унилатеральной и билатеральной ретинобластомой достоверно не различаются. Все мозаичные мутации, представлены нуль-аллелями; мозаичных миссенс-мутаций в нашей выборке не обнаружено. Не выявлено мозаичных мутаций в 1-м и 2-м экзонах гена RB1, расположенных проксимальнее альтернативного промотора, импринтинг которого определяет пенетрантность мутаций в зависимости от родительского происхождения мутантного аллеля. Заключение. Применение глубокого ВПС в сочетании с усовершенствованным алгоритмом анализа результатов, направленным на выявление мозаичных мутаций, повышает эффективность ДНК-диагностики ретинобластомы, способствуя совершенствованию медико-генетического консультирования и лечения больных. Background. Sporadic retinoblastoma develops as a result of de novo mutations in both alleles of the RB1 gene. Often in sporadic retinoblastoma, the initial mutation in RB1 is mosaic, that is, it is formed in a postzygotic, early embryonic cell, which leads to an uneven distribution of mutant clones between different tissues of the body. The ability to identify a mosaic variant of a mutation in the RB1 gene is important for both medical genetic counseling and clinical management of patients, since mosaicism affects the development of the clinical picture of the disease, the risk of developing a tumor in the other eye, as well as other tumors, and the risk of mutation transmission to the next generation. Aim: to establish the frequency and spectrum of somatic mosaic mutations in the RB1 gene in patients with sporadic retinoblastoma and to quantify the content of the mutant allele in cases with mosaicism. Methods. The study was carried out on the DNA of blood lymphocytes from patients with sporadic retinoblastoma. Screening of point mutations, small insertions/deletions in the RB1 gene was performed by semiconductor high-throughput parallel sequencing (NGS). Exclusion of gross deletions in the RB1 gene was performed by MLPA. To search for mosaic mutations with a very low representation (less than 10%) of the mutant allele, an in-depth analysis of the NGS data was developed an in-house algorithm based on bioinformatic and statistical approaches. To verify mosaic pathogenic mutations identified with NGS, Sanger sequencing was used. Results. Mosaic mutations were found more common among patients with sporadic unilateral form of retinoblastoma than in those with sporadic bilateral form; the differences are statistically significant. At the same time, the frequencies of mosaic mutations with a high and low representation of mutant alleles between the groups of patients with unilateral and bilateral retinoblastoma did not differ significantly. All mosaic mutations are null alleles; mosaic missense mutations were not found in our patients’ cohort. No mosaic mutations were detected in the 1st and 2nd exons of the RB1 gene, located proximal to the alternative promoter, the imprinting of which determines the penetrance of mutations depending on the parental origin of the mutant allele. Conclusion. The use of deep high-throughput parallel sequencing in combination with an improved algorithm for analyzing the NGS results, aimed at identifying mosaic mutations, increases the efficiency of DNA diagnostics of retinoblastoma, contributing to the improvement of medical genetic counseling and treatment of patients.

STRUCTURE OF HEREDITARY AND CONGENITAL PATHOLOGY IN A MULTIDISCIPLINARY SPECIALIZED PEDIATRIC CLINIC: PERSONALIZED APPROACH TO DIAGNOSTICS

Hereditary and congenital pathologies make up a significant proportion in the structure of the general morbidity and mortality of the child population. In this regard, the problem of personalized medical care in multidisciplinary clinical centers seems very urgent. In the Scientific-Practical Center of specialized medical care for children the medical genetic service successfully functions since 1995. In 2017–2019, patients were consulted by geneticists, which accounted for 10,6% of all discharged patients; karyotype studies were performed in 463 (20,4%) consulted patients, chromosomal pathology was revealed in 28 (6,04%) of all karyotyped patients. DNA research was performed in 188 patients: exome sequencing – in 112; sequencing of exons of the SCN1A gene – in 39; search for mutations in the PHOX2B gene – in 17; search for frequent mutations in the FGFR1,2,3 genes – in 15 (the technique was introduced since September 2018); sequencing of SLC2A1 gene – in 5 patients. The high demand for medical genetic counseling and laboratory genetic diagnosis of hereditary and congenital diseases confirms the need for independent medical genetic units in multidisciplinary clinical hospitals, that should interact with medical genetic services at regional and federal levels.

Telemedicine – chances and challenges for medical genetics in Germany

Telemedicine has been in practical use for many years, mostly within the context of model projects. The current Covid-19 pandemic has accelerated the process of implementing telemedicine in standard care. Numerous regulations, as well as complex reimbursement structures play a role in the application of telemedicine in medical genetics in Germany. Discipline- and technology-specific challenges complicate the integration of technical solutions into the medical genetic practice. In previous studies teleconsultations and virtual consultations in medical genetics have proven their value as indicated by high levels of satisfaction in the users and showing no inferiority to in-person consultation in terms of psychosocial outcome. The next years will bring an increasing demand for genetic counseling that can hardly be met by the limited number of specialists in Germany. In this context telemedicine can help to close these gaps in standard care while strengthening the field by ensuring comprehensive medical genetic care. The German medical genetics community is asked to actively shape the process of implementation by defining areas of genetic counseling that are suitable for telemedicine, by regulating access for physicians and by contributing to the renumeration structures.

Telegenetics for inherited retinal diseases in the COVID-19 environment

Inherited retinal diseases (IRDs) are visually debilitating conditions that affect families worldwide. They require extensive clinical testing, examination, and patient and family counseling, which are frequently accomplished over single-day extended clinic visits. However, the COVID-19 pandemic has limited the number of patients and staff allowed in clinics, leading to interruptions in care. We therefore developed telehealth management protocols for complete or hybrid virtual visits. The three main components of our telegenetics approach included reviewing the diagnostic tests results remotely, in-person or virtual video visits with a retina specialist, and virtual genetic testing using saliva kits. During the first 5 months of the program, telegenetic care was provided for 80 patients, including 3 international patients, and a spectrum of retinal dystrophies were diagnosed and managed. In conclusion, telegenetic virtual visits ensure continuity of care while reducing patient and provider exposure to SARS-CoV-2 and may continue and expand into other medical genetic conditions long after the pandemic.