Factors Affecting Genetic Consultation in Adolescent and Young Adult Patients With Sarcoma

Background: Given a link between sarcomas and hereditary cancer predisposition syndromes, including Li-Fraumeni syndrome, the consideration for genetic counseling is recommended for all adolescent and young adult (AYA) patients diagnosed with sarcoma. The aim of this study was to evaluate factors influencing genetic consultations in AYA patients with sarcoma at the University of Wisconsin (UW). Methods: A retrospective chart review was performed on AYA patients diagnosed with sarcoma between the ages of 15 and 39 years who were seen at least once between 2015 to 2019 at UW. Our chart review identified discussions regarding genetics, referrals to genetics, genetic consultations, and results of genetic testing. Variables hypothesized to affect patient referrals for genetic consultation were identified a priori. Descriptive statistical methods and a univariate analysis were used to identify patient characteristics associated with genetic counseling referral. Results: We identified 87 AYA patients with sarcoma. Only 19 (22%) of these patients had documentation of a discussion about genetics, 15 (17%) of whom were subsequently referred for genetic consultation. Of these 15 patients, 9 (60%) were seen in consultation. All 9 patients seen by genetics underwent genetic testing, with 4 (44%) of these patients having identified heritable cancer predisposition syndromes. Likelihood for genetics referral was linked most strongly to documented genetics discussion with an oncology provider (P<.001). Conclusions: Despite the recommendation for consideration for genetic counseling in AYA patients with sarcoma, <25% of such patients in our study had a documented discussion about genetics. Supporting this need, all referred patients met criteria for genetic testing, and 44% of tested patients were found to have a heritable cancer predisposition syndrome. These data support the initial conversation by a provider as critical to genetic referral and suggest the need for more specific national recommendations for the genetic evaluation of all AYA patients with sarcoma.

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).

Evaluation and comparison of hereditary Cancer guidelines in the population

Background Family health history (FHx) is an effective tool for identifying patients at risk of hereditary cancer. Hereditary cancer clinical practice guidelines (CPG) contain criteria used to evaluate FHx and to make recommendations for genetic consultation. Comparing different CPGs used to evaluate a common set of FHx provides insight into how well the CPGs perform, the extent of agreement across guidelines, and how well they identify patients who should consider a cancer genetic consultation. Methods We compare the American College of Medical Genetics and Genomics (ACMG) and the National Comprehensive Cancer Networks (NCCN) (2019) CPG criteria for FHx collected by a chatbot and evaluated by ontologies and web services in a previous study. Collected FHx met criteria from seven groups: Gene Mutation, Breast and Ovarian, Li-Fraumeni syndrome (LFS), Colorectal and Endometrial, Relative Meets Criteria, ACMG Only Criteria, and NCCN Testing. CPG Criteria were coded and matched across 12 ACMG sub-guidelines and 6 NCCN sub-guidelines for comparison purposes. Results The dataset contains 4915 records, of which 2221 met either ACMG or NCCN criteria and 2694 did not. There was significant overlap—1179 probands met both ACMG and NCCN criteria. The greatest similarities were for Gene Mutation and Breast and Ovarian criteria and the greatest disparity existed among Colorectal and Endometrial criteria. Only 156 positive gene mutations were reported and of the 2694 probands who did not meet criteria, 90.6% of them reported at least one cancer in their personal or family cancer history. Conclusion Hereditary cancer CPGs are useful for identifying patients at risk of developing cancer based on FHx. This comparison shows that with the aid of chatbots, ontologies, and web services, CPGs can be more efficiently applied to identify patients at risk of hereditary cancer. Additionally this comparison examines similarities and differences between ACMG and NCCN and shows the importance of using both guidelines when evaluating hereditary cancer risk.

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.

Strategies in Rapid Genetic Diagnostics of Critically Ill Children: Experiences From a Dutch University Hospital

Background: Genetic disorders are a substantial cause of infant morbidity and mortality and are frequently suspected in neonatal intensive care units. Non-specific clinical presentation or limitations to physical examination can result in a plethora of genetic testing techniques, without clear strategies on test ordering. Here, we review our 2-years experiences of rapid genetic testing of NICU patients in order to provide such recommendations.Methods: We retrospectively included all patients admitted to the NICU who received clinical genetic consultation and genetic testing in our University hospital. We documented reasons for referral for genetic consultation, presenting phenotypes, differential diagnoses, genetic testing requested and their outcomes, as well as the consequences of each (rapid) genetic diagnostic approach. We calculated diagnostic yield and turnaround times (TATs).Results: Of 171 included infants that received genetic consultation 140 underwent genetic testing. As a result of testing as first tier, 13/14 patients received a genetic diagnosis from QF-PCR; 14/115 from SNP-array; 12/89 from NGS testing, of whom 4/46 were diagnosed with a small gene panel and 8/43 with a large OMIM-morbid based gene panel. Subsequent secondary or tertiary analysis and/or additional testing resulted in five more diagnoses. TATs ranged from 1 day (QF-PCR) to a median of 14 for NGS and SNP-array testing, with increasing TAT in particular when many consecutive tests were performed. Incidental findings were detected in 5/140 tested patients (3.6%).Conclusion: We recommend implementing a broad NGS gene panel in combination with CNV calling as the first tier of genetic testing for NICU patients given the often unspecific phenotypes of ill infants and the high yield of this large panel.

Prevalence of congenital absence of vas deferens and related genetic factors among male infertilities: A systematic review

A systematic review was conducted to describe the prevalence of congenital absence of vas deferens (CAVD) and types of cystic fbrosis transmembrane conductance regulator (CFTR) gene mutation, Adhesion G-protein coupled receptor G2 (ADGRG2) mutation leading to CAVD among male infertilities aimed at providing comprehensive counseling in the treatment of male infertility. Information and data from eligible publications were searched and selected from the PubMed and Medline e-library from 2010 to 2020 by using 8 main keywords. The results showed that the prevalence of CAVD was approximately 0.1% in male and about 80% of congenital bilateral absences of the vas deferens (CABVD) patients had the CFTR mutation. These mutations were recessive gene abnormalities on the long arm of chromosome 7. Besides the mutation, recent researches showed the mutation of the ADGRG2 gene on X chromosome also led to CBAVD. It was approximately 10 - 20% of CBAVD and 60 - 70% of the congenital unilateral absence of the vas deferens (CUAVD) that was still not diagnosed genetically. In conclusion, the genetic consultation is necessary for CAVD patients before deciding to have a baby

Clinical value of a screening tool for tumor predisposition syndromes in childhood cancer patients (TuPS): a prospective, observational, multi-center study

Recognizing a tumor predisposition syndrome (TPS) in a child with cancer is of clinical relevance. Earlier we developed a screening tool to increase diagnostic accuracy and clinical efficiency of identifying TPSs in children with cancer. Here we report on the value of this tool in clinical practice. TuPS is a prospective, observational, multi-center study including children newly diagnosed with cancer from 2016 to 2019 in the Netherlands. Children in whom a TPS had been diagnosed before the cancer diagnosis were excluded. The screening tool consists of a checklist, 2D and 3D photographic series and digital assessment of these by a clinical geneticist. If a TPS was suspected, the patient was assessed positive and referred for routine genetic consultation. Primary aim was to assess the clinical value of this new screening tool. Of the 363 included patients, 57% (208/363) were assessed positive. In 15% of patients (32/208), the 2D photographic series with (n = 12) or without (n = 20) 3D photographs were decisive in the positive assessment. In 2% (4/208) of positive assessed patients, a TPS was diagnosed, and in an additional 2% (4/208) a germline variant of uncertain significance was found. Thirty-five negatively assessed patients were evaluated through routine genetic consultation as controls, in none a TPS was detected. Using the screening tool, 57% of the patients were assessed as suspected for having a TPS. No false negative results were identified in the negative control group in the clinical care setting. The observed prevalence of TPS was lower than expected, due to selection bias in the cohort.

Ethics of Uncertainty As an Extension of Virtue Epistemology

Uncertainty can’t be understood without taking into account both properties of the problem situation and agent’s knowledge about it. The correspondence of knowledge and situation of decision-making is crucial for understanding the onto-epistemological nature of uncertainty. At the same time, this correspondence is the key topic in virtue epistemology, especially in its ‘non-classical’, regulatory, branch, related to works of R. Roberts and W.J. Wood. In this article, genetic consultation is chosen as an example of such a problematic situation since a doctor and a patient explicitly deal with the uncertainty of genetic risks. The problems of communication and joint decision-making in the context of medical-genetic consultation are comprehensively described in bioethics. At the same time, its social dimension is limited to the direct interaction of two individual agents, that allows us to use it as a model for constructing the ethics of uncertainty. In this article, four forms of uncertainty are identified: descriptive, normative and radical uncertainties, and translation uncertainty. Referring to the approaches of virtue epistemology, the author brings each of these forms into conformity with the proposed regulatory principle. The regulations assume that generating or disseminating knowledge under conditions of uncertainty require taking into account the incompleteness of the presented model of reality in its four aspects. A modelled fragment of reality could change in a predictable (descriptive uncertainty) or unexpected (radical uncertainty) way. The goals and values of a model’s user can not be hierarchically ordered, and may also change in the future (normative uncertainty). User’s interpretations of the model may be diverse, and can never be strictly defined by the intentions of the model’s author (indeterminancy of translation, or uncertainty whether success of co-reference is achieved).

MEDICAL AND GENETIC CONSULTING IN THE CLINICAL PRACTICE OF AN ANDROLOGIST

There is a system of genetic consultation, which includes diagnostics, defining the type of heredity and prognosis for family. Genetic consultation must help in 8-10% of all families. The staff on MGC consists in clinical genetic, cytogenetic, pediatrician, gynaecologist and other specialists. The main task of genetic consultation is prevention of hereditary diseases.