Clinical Guideline for Preimplantation Genetic Testing in Inherited Cardiac Diseases.

BACKGROUND: Preimplantation genetic testing (PGT) is a reproductive technology that selects embryos without (familial) genetic variants. PGT has been applied in inherited cardiac disease and is included in the latest American Heart Association/American College of Cardiology guidelines. However, guidelines selecting eligible couples who will have the strongest risk reduction most from PGT are lacking. We developed an objective decision model to select eligibility for PGT and compared its results with those from a multidisciplinary team. METHODS: All couples with an inherited cardiac disease referred to the national PGT center were included. A multidisciplinary team approved or rejected the indication based on clinical and genetic information. We developed a decision model based on published risk prediction models and literature, to evaluate the severity of the cardiac phenotype and the penetrance of the familial variant in referred patients. The outcomes of the model and the multidisciplinary team were compared in a blinded fashion. RESULTS: Eighty-three couples were referred for PGT (1997-2022), comprising 19 different genes for 8 different inherited cardiac diseases (cardiomyopathies and arrhythmias). Using our model and proposed cutoff values, a definitive decision was reached for 76 (92%) couples, aligning with 95% of the multidisciplinary team decisions. In a prospective cohort of 11 couples, we showed the clinical applicability of the model to select couples most eligible for PGT. CONCLUSIONS: The number of PGT requests for inherited cardiac diseases increases rapidly, without the availability of specific guidelines. We propose a 2-step decision model that helps select couples with the highest risk reduction for cardiac disease in their offspring after PGT.

Carrier burden of over 300 diseases in Han Chinese identified by expanded carrier testing of 300 couples using assisted reproductive technology.

BACKGROUND: Expanded carrier screening (ECS) has become a common practice for identifying carriers of monogenic diseases. However, existing large gene panels are not well-tailored to Chinese populations. In this study, ECS testing for pathogenic variants of both single-nucleotide variants (SNVs) and copy number variants (CNVs) in 330 genes implicated in 342 autosomal recessive (AR) or X-linked diseases was carried out. We assessed the differences in allele frequencies specific to the Chinese population who have used assisted reproductive technology (ART) and the important genes to screen for in this population. METHODOLOGY: A total of 300 heterosexual couples were screened by our ECS panel using next-generation sequencing. A customed bioinformatic algorithm was used to analyze SNVs and CNVs. Guidelines from the American College of Medical Genetics and Genomics and the Association for Molecular Pathology were adapted for variant interpretation. Pathogenic or likely pathogenic (P/LP) SNVs located in high homology regions/deletions and duplications of one or more exons in length were independently verified with other methods. RESULTS: 64.83% of the patients were identified to be carriers of at least one of 342 hereditary conditions. We identified 622 P/LP variants, 4.18% of which were flagged as CNVs. The rate of at-risk couples was 3%. A total of 149 AR diseases accounted for 64.05% of the cumulative carrier rate, and 48 diseases had a carrier rate above 1/200 in the test. CONCLUSION: An expanded screening of inherited diseases by incorporating different variant types, especially CNVs, has the potential to reduce the occurrence of severe monogenic diseases in the offspring of patients using ART in China.

Enfermedad de Rendu-Osler-Weber con presentación inusual / Rendu-Osler-Weber´s disease with unusual presentation

La enfermedad de Rendu-Osler-Weber, también conocido como telangiectasia hemorrágica hereditaria, es una enfermedad genética de herencia autosómica dominante con penetrancia incompleta. Afecta por igual a ambos sexos y los síntomas se inician habitualmente entre los 20 y 40 años, pero se considera que la enfermedad está infradiagnosticada. Típicamente las formas clínicas y el debut de esta enfermedad se asocian a los órganos y tejidos que se afectan con mayor frecuencia: telangiectasias en mucosas y en piel, epistaxis, sangramiento gastrointestinal, pulmonar e intracerebral. En contraste, el caso clínico que se presenta se caracteriza porque las primeras manifestaciones clínicas que motivaron la consulta médica fueron crisis de dolores e inflamación ósea en el miembro superior derecho, lo cual es inusual y se inscribe como un elemento de novedad en la enfermedad. Es el objetivo de esta publicación exponer un caso de telangiectasia hemorrágica hereditaria con una forma de presentación atípica en una adolescente. Al alta hospitalaria, la paciente estaba estable, sin complicaciones. Se recomendó seguimiento hospitalario fundamentalmente por la especialidad de Neumología, por ser los pulmones los órganos más afectados(AU)

Rendu-Osler-Weber´s disease, also known as hereditary hemorrhagic telangiectasia, is a genetic disease of autosomal dominant inheritance with incomplete penetrance. It affects both sexes equally and symptoms usually begin between the ages of 20 and 40, but it is considered that the disease is underdiagnosed. Typically, the clinical forms and the onset of this disease are associated with the organs and tissues that are most frequently affected: mucosal and skin telangiectasias, epistaxis, gastrointestinal, pulmonary and intracerebral bleeding. In contrast, the clinical case that is presented is characterized because the first clinical manifestations that motivated the medical consultation were crises of pain and bone inflammation in the right upper limb, which is unusual and is inscribed as an element of novelty in the disease. The objective of this publication is to present a case of hereditary hemorrhagic telangiectasia with an atypical presentation in a female teenager(AU)

Diagnóstico ecográfico prenatal en el Centro Municipal de Genética Médica de Marianao, La Habana / Prenatal Ultrasound Diagnosis at the Genetics Center of Marianao Municipality, Havana

Introducción: La ecografía prenatal en el Programa de Prevención de Enfermedades Genéticas permite la detección precoz de malformaciones congénitas y mejora la calidad de vida de la madre y su familia. Objetivo: Conocer la frecuencia de malformaciones congénitas diagnosticadas en el Centro de Genética de Marianao y compararla con las estadísticas nacionales e internacionales. Métodos: Estudio retrospectivo, descriptivo y observacional. Se cuantificaron 203 malformaciones diagnosticadas entre 2007 y 2017 en el Centro de Genética de Marianao. Se consideraron como variables la edad materna, la edad gestacional del diagnóstico, la frecuencia por años y los tipos de malformaciones por sistemas. Resultados: En 13 307 nacimientos se diagnosticaron 203 fetos malformados (1,52 por ciento) a una edad gestacional media de 20,15 semanas. Las malformaciones más frecuentes fueron neurológicas (27,1 por ciento) y cardiovasculares (16,2 por ciento). En las madres adolescentes predominaron las cardiovasculares (27,3 por ciento) y digestivas (16,2 por ciento en las madres añosas, las cromosómicas (57,1 por ciento). Antes de la semana 17 se diagnosticaron malformaciones digestivas (41,7 por ciento) y neurológicas (40 por ciento); entre las 18 y 21 semanas, las esqueléticas (41,2 por ciento); entre las 22 y 26 semanas, cardiovasculares (66,7 por ciento) y cromosómicas (52,4 por ciento) y, después de la semana 27, las renales (9 por ciento. Conclusión: Predominaron las malformaciones neurológicas y cardiovasculares. La edad materna media fue superior en las malformaciones cromosómicas y menor en las digestivas y cardiovasculares. En el primer marcador del programa se diagnosticó la mayoría de las malformaciones digestivas y neurológicas; y en el segundo marcador, las cardiovasculares, cromosómicas y esqueléticas(AU)

Introduction: Prenatal ultrasound in the Genetic Disease Prevention Program allows early detection of congenital malformations and improves the quality of life of the mother and her family. Objective: To know the frequency of congenital malformations diagnosed at the Genetics Center of Marianao Municipality, Havana, Cuba, and to compare it with national and international statistics. Methods: Retrospective, descriptive and observational study. A total of 203 malformations diagnosed between 2007 and 2017 at the Genetics Center of Marianao were quantified. Maternal age, gestational age at diagnosis, frequency by years and types of malformations by systems were considered as variables. Results: In 13,307 births, 203 malformed fetuses were diagnosed (1.52 percent), at a mean gestational age of 20.15 weeks. The most frequent malformations were neurological (27.1 percent) and cardiovascular (16.2 percent). Cardiovascular (27.3 percent) and digestive (16.2 percent) malformations predominated in adolescent mothers, while chromosomal malformations predominated in older mothers (57.1 percent). Before the seventeenth week, digestive (41.7 percent) and neurological (40 percent) alformations were diagnosed; between the eighteenth and twenty-first weeks, skeletal (41.2 percent) malformations were diagnosed; between the twenty-second and twenty-sixth weeks, cardiovascular (66.7 percent) and chromosomal (52.4 percent) malformations were diagnosed; and after the twenty-seventh week, renal (9 percent) malformations were diagnosed. Conclusion: Neurological and cardiovascular malformations prevailed. The mean maternal age was higher in chromosomal malformations, and lower in digestive and cardiovascular malformations. Most of the digestive and neurological malformations were diagnosed in the first marker of the Program, while cardiovascular, chromosomal and skeletal malformations were diagnosed in the second marker(AU)

Correction of Heritable Epigenetic Defects Using Editing Tools.

Epimutations refer to mistakes in the setting or maintenance of epigenetic marks in the chromatin. They lead to mis-expression of genes and are often secondary to germline transmitted mutations. As such, they are the cause for a considerable number of genetically inherited conditions in humans. The correction of these types of epigenetic defects constitutes a good paradigm to probe the fundamental mechanisms underlying the development of these diseases, and the molecular basis for the establishment, maintenance and regulation of epigenetic modifications in general. Here, we review the data to date, which is limited to repetitive elements, that relates to the applications of key editing tools for addressing the epigenetic aspects of various epigenetically regulated diseases. For each approach we summarize the efforts conducted to date, highlight their contribution to a better understanding of the molecular basis of epigenetic mechanisms, describe the limitations of each approach and suggest perspectives for further exploration in this field.

Partners in care.

This festschrift contribution, written for my colleague and mentor John Graham, reflects on geneticist-genetic counselor interactions in clinical care, samples of alternative models of care for pediatric and general genetic counselors, and avenues for expanding access to genetic healthcare services utilizing genetic counselors.

Clinical Practice Guidelines for Prenatal Aneuploidy Screening and Diagnostic Testing from Korean Society of Maternal-Fetal Medicine: (2) Invasive Diagnostic Testing for Fetal Chromosomal Abnormalities.

The Korean Society of Maternal Fetal Medicine proposed the first Korean guideline on prenatal aneuploidy screening and diagnostic testing, in April 2019. The clinical practice guideline (CPG) was developed for Korean women using an adaptation process based on good-quality practice guidelines, previously developed in other countries, on prenatal screening and invasive diagnostic testing for fetal chromosome abnormalities. We reviewed current guidelines and developed a Korean CPG on invasive diagnostic testing for fetal chromosome abnormalities according to the adaptation process. Recommendations for selected 11 key questions are: 1) Considering the increased risk of fetal loss in invasive prenatal diagnostic testing for fetal genetic disorders, it is not recommended for all pregnant women aged over 35 years. 2) Because early amniocentesis performed before 14 weeks of pregnancy increases the risk of fetal loss and malformation, chorionic villus sampling (CVS) is recommended for pregnant women who will undergo invasive prenatal diagnostic testing for fetal genetic disorders in the first trimester of pregnancy. However, CVS before 9 weeks of pregnancy also increases the risk of fetal loss and deformity. Thus, CVS is recommended after 9 weeks of pregnancy. 3) Amniocentesis is recommended to distinguish true fetal mosaicism from confined placental mosaicism. 4) Anti-immunoglobulin should be administered within 72 hours after the invasive diagnostic testing. 5) Since there is a high risk of vertical transmission, an invasive prenatal diagnostic testing is recommended according to the clinician's discretion with consideration of the condition of the pregnant woman. 6) The use of antibiotics is not recommended before or after an invasive diagnostic testing. 7) The chromosomal microarray test as an alternative to the conventional cytogenetic test is not recommended for all pregnant women who will undergo an invasive diagnostic testing. 8) Amniocentesis before 14 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 9) CVS before 9 weeks of gestation is not recommended because it increases the risk of fetal loss and malformation. 10) Although the risk of fetal loss associated with invasive prenatal diagnostic testing (amniocentesis and CVS) may vary based on the proficiency of the operator, the risk of fetal loss due to invasive prenatal diagnostic testing is higher in twin pregnancies than in singleton pregnancies. 11) When a monochorionic twin is identified in early pregnancy and the growth and structure of both fetuses are consistent, an invasive prenatal diagnostic testing can be performed on one fetus alone. However, an invasive prenatal diagnostic testing is recommended for each fetus in cases of pregnancy conceived via in vitro fertilization, or in cases in which the growth of both fetuses differs, or in those in which at least one fetus has a structural abnormality. The guidelines were established and approved by the Korean Academy of Medical Sciences. This guideline is revised and presented every 5 years.

[Prevention of genetic diseases : the return of the family practitioner ?] / Prévention des maladies génétiques. Le retour du médecin de famille ?

BACKGROUND: Information to kin is one of the major ethical problems of the new genetics. In France, the revised bioethics law in 2011 created the possibility for patients to authorize professionals, under certain conditions, to directly contact their relatives at risk. Beyond this, other actors, such as GPs, could however play a role in this process. METHODS: Our article is based on an ethnographic-type sociological study by observations and semi-structured interviews with patients (n=59) and genetic professionals (n=16) that took place from 2014 to 2016 in three genetic hospital wards in France and Canada. It focuses particularly on genetic predispositions to breast and ovarian cancers as well as genetic hemochromatosis. RESULTS: Because of its position as a primary care specialist, the general practitioner can play a decisive role in the process of informing relatives about genetic disorders. Upstream of the genetic test, the generalist, thanks to his knowledge of the family context of his patients, can play a referral role towards a specialized consultation. Downstream, it can also ensure a more effective follow-up of the information procedures undertaken by its patients thanks to the medical follow-up that it carries out. CONCLUSION: The data collected during our study highlight the unprecedented place that could be that of the general practitioner in the field of prevention in genetics. At the articulation between primary care and highly specialized care, it is the figure of the "family" doctor who seems to be called here to be renewed by genetics.

The Reproductive Journey in the Genomic Era: From Preconception to Childhood.

It is estimated that around 10-15% of the population have problems achieving a pregnancy. Assisted reproduction techniques implemented and enforced by personalized genomic medicine have paved the way for millions of infertile patients to become parents. Nevertheless, having a baby is just the first challenge to overcome in the reproductive journey, the most important is to obtain a healthy baby free of any genetic condition that can be prevented. Prevention of congenital anomalies throughout the lifespan of the patient must be a global health priority. Congenital disorders can be defined as structural or functional anomalies that occur during intrauterine life and can be identified prenatally, at birth, or sometimes may only be detected later during childhood. It is considered a frequent group of disorders, affecting 3-6% of the population, and one of the leading causes of morbidity and mortality. Congenital anomalies can represent up to 30-50% of infant mortality in developed countries. Genetics plays a substantial role in the pathogenesis of congenital anomalies. This becomes especially important in some ethnic communities or populations where the incidence and levels of consanguinity are higher. The impact of genetic disorders during childhood is high, representing 20-30% of all infant deaths and 11.1% of pediatric hospital admissions. With these data, obtaining a precise genetic diagnosis is one of the main aspects of a preventive medicine approach in developed countries. The field of reproductive health has changed dramatically from traditional non-molecular visual microscope-based techniques (i.e., fluorescence in situ hybridization (FISH) or G-banding karyotype), to the latest molecular high-throughput techniques such as next-generation sequencing (NGS). Genome-wide technologies are applied along the different stages of the reproductive health lifecycle from preconception carrier screening and pre-implantation genetic testing, to prenatal and postnatal testing. The aim of this paper is to assess the new horizon opened by technologies such as next-generation sequencing (NGS), in new strategies, as a genomic precision diagnostic tool to understand the mechanisms underlying genetic conditions during the "reproductive journey".

The Impact of Next-Generation Sequencing on the Diagnosis, Treatment, and Prevention of Hereditary Neuromuscular Disorders.

The impact of high-throughput sequencing in genetic neuromuscular disorders cannot be overstated. The ability to rapidly and affordably sequence multiple genes simultaneously has enabled a second golden age of Mendelian disease gene discovery, with flow-on impacts for rapid genetic diagnosis, evidence-based treatment, tailored therapy development, carrier-screening, and prevention of disease recurrence in families. However, there are likely many more neuromuscular disease genes and mechanisms to be discovered. Many patients and families remain without a molecular diagnosis following targeted panel sequencing, clinical exome sequencing, or even genome sequencing. Here we review how massively parallel, or next-generation, sequencing has changed the field of genetic neuromuscular disorders, and anticipate future benefits of recent technological innovations such as RNA-seq implementation and detection of tandem repeat expansions from short-read sequencing.

Socioeconomic status and uptake of reproductive carrier screening in Australia.

Reproductive carrier screening enables the early identification of genetic conditions that may impact the long-term health of a child, including cystic fibrosis, fragile X syndrome, and spinal muscular atrophy. We used unique data from the major providers of pathology services in Australia to profile women who intend on becoming, or who are, pregnant and access basic to advanced testing for genetic conditions. We found a strong socioeconomic gradient in the uptake of reproductive carrier screening, with women living in the most advantaged postcodes across Australia significantly being more likely to have reproductive carrier screening than those living in the most disadvantaged areas. These results highlight the need to minimise social and financial barriers that are currently limiting access.

Management of Secondary Genomic Findings.

Secondary genomic findings are increasingly being returned to individuals as opportunistic screening results. A secondary finding offers the chance to identify and mitigate disease that may otherwise be unrecognized in an individual. As a form of screening, secondary findings must be considered differently from sequencing results in a diagnostic setting. For these reasons, clinicians should employ an evaluation and long-term management strategy that accounts for both the increased disease risk associated with a secondary finding and the lower positive predictive value of a screening result compared to an indication-based testing result. Here we describe an approach to the clinical evaluation and management of an individual who presents with a secondary finding. This approach enumerates five domains of evaluation-(1) medical history, (2) physical exam, (3) family history, (4) diagnostic phenotypic testing, and (5) variant correlation-through which a clinician can distinguish a molecular finding from a clinicomolecular diagnosis of genomic disease. With this framework, both geneticists and non-geneticist clinicians can optimize their ability to detect and mitigate genomic disease while avoiding the pitfalls of overdiagnosis. Our goal with this approach is to help clinicians translate secondary findings into meaningful recognition, treatment, and prevention of disease.

The Israeli national population program of genetic carrier screening for reproductive purposes. How should it be continued?

The Israeli population genetic screening program for reproductive purposes, is a population-specific screening that includes all known, severe diseases and relatively frequent in a specific population (carrier frequency at or above 1:60 and/or disease frequency at or above 1 in 15,000 live births). The carrier screening program is free of charge and offers testing according to disease frequency in the different groups within the population.The extraordinary technical changes that occurred in the last decade as well as the changes in the type of marriages within the Israeli population necessitate a revision in the basis of the program.The screening should include instead of only the relatively frequent variants, all the variants that were reported among patients causing a severe disease for which the natural history is well known without regard of their frequency. The population-specific screening that determine which variants are included according to the origin of the couple should be abandoned for a general screening including either all the Jewish population or all the Israeli Arab population.

Riesgo preconcepcional genético como herramienta de prevención en la Atención Materno Infantil / Preconception genetic risk as a prevention tool in mother and child care

Introducción: El primer programa de prevención para las enfermedades genéticas y defectos congénitos en Cuba se logra cuando el programa de Atención Materno Infantil alcanza el máximo de condiciones en 1981. Objetivo: Incrementar los conocimientos sobre el riesgo preconcepcional genético en el personal de enfermería Métodos: Se realizó un estudio cuasi experimental de tipo intervención educativa en enfermería en el Policlínico Universitario José Martí Pérez sobre la identificación de los factores de riesgo preconcepcional genético, en Santiago de Cuba, en el segundo semestre del 2017. El universo estuvo constituido por la plantilla física de la institución (150 enfermeras), seleccionando una muestra por conveniencia de 34 enfermeras en el Grupo Básico de Trabajo # I (GBT); se procedió a la aplicación del instrumento de evaluación para identificar las necesidades de aprendizaje sobre los riesgos genéticos, diseñando y aplicando un Programa de Capacitación, evaluando antes y después de la intervención. Resultados: Predominaron las enfermeras generales de más de 50 años con conocimientos inadecuados, antes de la intervención, sobre los elementos que influyen, el momento en que acontece el riesgo preconcepcional genético, así como, los conocimientos sobre el riesgo prenatal, en el recién nacido y en las enfermedades comunes. Conclusiones: Luego de aplicada la estrategia de intervención se lograron elevar los conocimientos sobre el riesgo preconcepcional genético en algunos miembros de la muestra, que incorporaron lo aprendido a las diferentes actividades y procesos asistenciales en la comunidad(AU)

Introduction: The first Cuban program for prevention of genetic diseases and defects was started when the mother and child care program achieved an optimal status in the year 1981. Objective: Broaden knowledge about preconception genetic risk among the nursing personnel. Methods: A quasi-experimental study was conducted based on an educational intervention in nursing at José Martí Pérez University Polyclinic. The study aimed to identify preconception genetic risks in Santiago de Cuba during the second semester of 2017. The study universe was the physical payroll of the institution (150 nurses), of whom 34 from Basic Work Team (BWT) No. 1 were selected by convenience sampling. The evaluation tool was applied to identify learning gaps related to genetic risks. Next, a training program was designed and applied. Participants in the study were evaluated before and after the intervention. Results: A predominance was found of general nurses of over 50 years' experience with poor pre-intervention knowledge about the factors involved in preconception genetic risks and the moment when such risks occur, or about prenatal and newborn risks and common diseases. Conclusions: Upon application of the intervention strategy, knowledge about preconception genetic risk was broadened among some members of the sample, who incorporated the newly-acquired information into the various community care activities and processes(AU)

[Main methodological approaches to the identification and diagnosis of monogenic hereditary diseases and problems in the organization of medical care and unified preventive programs].

In order to optimize economic and organizational technologies for the provision of medical care to the population and to increase the effectiveness of preventive programs, an analysis of the accumulated morbidity and prevalence of monogenic hereditary diseases (MHDs) has been carried out in 13 federal subjects of the Russian Federation representing 11 ethnic groups: Russians of 6 regions, Tatars, Maris, Chuvashs, Bashkirs, Udmurts, Abazins, Adygeans, Nogays, Circassians and Karachays. The study of the population was carried out according to the developed protocol of complex genetic and epidemiological studies in the Research Center for Medical Genetics, which remains unchanged throughout the study. Here we have studied the structure of the genetic load and diversity of MHDs depending on the prevalence of diseases and in accordance with the classification by organ and system types of disease: neurological, ophthalmological, genodermatosis, skeletal, hereditary syndromes, and other hereditary pathology (metabolic hereditary diseases, disorders of blood, hearing, etc.). It is shown that the maximum number of patients (61.81%) falls in the group of frequent forms of MHDs, which differ by federal subjects / ethnic groups of the Russian Federation. There are frequent forms of MHDs for all populations, and "specific" forms for particular federal subjects of the Russian Federation/ethnic groups. Only for a small group of hereditary diseases there is treatment. Most of the detected diseases-psychiatric, neurological, hematological, and hereditary syndromes-significantly reduce life expectancy. Hereditary diseases of the skeleton, eyes, ears and metabolism affect the quality of life, adaptation in society and public health. On average, 65% of patients are diagnosed with MHDs for the first time. This situation implies changes in medical thinking, changes in education and development of both common for all regions and specific prevention programs. Thus, fundamental research in medicine can improve the quality of medical services and contribute to the improvement of public health.

Recomendaciones para el estudio genético e inmunológico en la disfunción reproductiva / Recommendations regarding the genetic and immunological study of reproductive dysfunction

Varios miembros de diferentes asociaciones científicas y expertos de la reproducción han actualizado las recomendaciones de estudio genético e inmunológico en las parejas con disfunción en la reproducción con el fin de mejorar la asistencia sanitaria. El estudio se ha considerado altamente recomendable cuando la prueba diagnóstica es relevante para la toma de decisiones, moderada cuando estas han mostrado un resultado poco consistente y baja, cuando el beneficio de la prueba es incierto. Con la indicación de estas recomendaciones obtendremos una información relevante para el diagnóstico, pronóstico y tratamiento de la pareja con disfunción en la reproducción

In this article several members of diverse scientific associations and reproduction experts from Spain have updated different genetic and immunological procedure recommendations in couples affected by reproductive dysfunction with the goal of providing a set of useful guidelines for the clinic. The laboratory test has been considered as highly recommendable for making clinical decisions when the result of the diagnostic test is relevant, moderately recommendable when the results are of limited evidence because they are inconsistent, and low when the benefit of the test is uncertain. It is expected that these recommendations will provide some useful guidelines for the diagnosis, prognosis and treatment of couples presenting reproductive dysfunction