The Role of Deep Phenotyping of Precision Medicine for Rare Bone Diseases / 罕见病研究

Deep phenotyping is a precise and comprehensive approach used for the precise analysis and comprehensive assessment of multi-system phenotypes of the patients. The approach uses symptoms, signs, various medical examination and laboratory results, and other relevant medical information. In the clinical diagnosis and medical research of rare bone diseases, deep phenotyping plays a pivotal role. The realization of precision medicine primarily comprises three key dimensions: deep phenotyping, stratified medicine, and targeted therapy. The deep phenotyping is the basis for the latter two. Deep phenotyping not only facilitates fine subtyping of diseases, but also allows for the in-depth understanding of genetic data. The use of deep phenotyping requires stand- ardized terminology and specific procedures. Moreover, deep phenotyping shows substantial potential using the application of artificial intelligence technology particularly when combining with multi-omics techniques.

Research advances in the clinical genetics of leukodystrophy in children / 中国当代儿科杂志

Leukodystrophy (LD) is a group of genetic heterogeneous diseases characterized by primary abnormalities in glial cells and myelin sheath, and it is a common nervous system disease in children and has significant genotype-phenotype correlation. In recent years, the improvement in high-throughput sequencing has changed the diagnostic and therapeutic mode of LD, and elaborative phenotype analysis, such as the collection of natural history and multimodal neuroimaging evaluation during development, also provides important information for subsequent genetic diagnosis. This article reviews LD from the perspective of clinical genetics, in order to improve the awareness of this disease among pediatricians in China.

Análisis molecular de familias uruguayas con Enfermedad de Huntington / Molecular analysis of the Uruguayan families with Huntington’s Disease

Introducción: La Enfermedad de Huntington (EH) es un trastorno neurodegenerativo; autosómico dominante, con expresividad variable y penetrancia completa. La prevalencia estimada es entre 1-4 cada 100.000 habitantes. Es causada por expansión de tripletes CAG en el exón 1 del gen IT-15 que conduce a la síntesis de una proteína con una región de poliglutaminas expandidas que forman agregados en el núcleo celular induciendo a la apoptosis. Los alelos normales presentan un número menor a 26 tripletes CAG, y aquellos con más de 40 conducirán siempre a la enfermedad. Alelos de entre 26 a 36 repetidos se consideran normales “mutables” y de 36 a 39 repetidos generan un riesgo aumentado de desarrollar la enfermedad. Objetivo: Poner a punto el diagnóstico molecular en una población uruguaya, mediante la determinación del tamaño exacto de la mutación en personas afectadas o con sospecha clínica de EH, mediante el uso de técnicas de biología molecular. Métodos: Pacientes de la Policlínica de Enfermedad de Parkinson y Movimientos Anormales del Hospital de Clínicas. La determinación del número de repetidos se realizó mediante técnicas de amplificación del ADN por PCR y posterior análisis en geles de poliacrilamida y secuenciación. Resultados: Realizamos el diagnóstico molecular de 16 pacientes, 15 con un diagnóstico clínico previo, y uno asintomático. Se descartó el diagnóstico de EH en otros dos individuos analizados. Conclusiones: Hemos logrado la puesta a punto del estudio molecular para la enfermedad de EH por primera vez en nuestro país. Esta prueba es de gran utilidad como diagnóstico confirmatorio, etiológico o diferencial de EH.

Introduction: Huntington disease (HD) is a neurodegenerative disorder with an autosomal dominant inheritance mode, complete penetrance and variable clinical expressivity. The estimated prevalence is 1 to 4 per 100.000 individuals. It is caused by a CAG triplet expansion in exon 1 of the IT-15 gene which codes for a protein with an enlarged polyglutamine region. This leads to the formation of protein aggregates in the cell nucleus and induces apoptosis. Normal alleles show less than 26 CAG repeats, and those over 40 always lead to the disease. Alleles with 26 to 36 repeats are considered normal “mutable” alleles and those between 36 to 39, are considered in a gray zone with increased risk of developing the disease. Aims: To develop a diagnosis of HD in a uruguayan population and determine the exact size of the mutation in clinically affected subjects using molecular biology techniques. Methods: Patients were derived from Neurology Clinic of the “Hospital de Clínicas”. The determination of the CAG repeat number was done using polymerase chain reaction (PCR) technique, subsequent analysis on polyacrilamide gels and sequencing. Results: We performed the molecular diagnosis in 18 patients with clinical suspicion of HD. Fifteen of them had a previous clinical diagnosis and one had no symptoms. Besides, in two additional individuals this test allowed us to discard HD. Conclusions: A molecular diagnostic for HD disease was developed for the first time in our country. This test is of great clinical utility as a confirmatory, etiological, or differential diagnosis.

Enfermedades genéticas en una población rural colombiana con discapacidad / Genetic disease in a disabled population from a Colombian rural area

La enfermedad genética, como causa de discapacidad, es un problema de salud real pero subestimado. Aún son insuficientes las intervenciones oportunas y adecuadas en pacientes con discapacidad de origen genético. El objetivo de este estudio fue determinar la prevalencia de enfermedad genética en una población discapacitada del área rural de Anapoima, Colombia. Se evaluaron 35 pacientes con diferentes tipos de discapacidad y sus familias. Los diagnósticos etiológicos de los pacientes se clasificaron en cinco categorías de acuerdo con la carga genética: categoría I (enfermedades monogénicas), II (enfermedades cromosómicas), III (enfermedades multifactoriales), IV (enfermedades con origen desconocido) y V (enfermedades ambientales). Una vez practicados los estudios de genética, se volvieron a clasificar bajo las mismas categorías. Antes de practicar los estudios de genética, las enfermedades se ubicaban, principalmente, en la categoría IV seguida de la II. Al finalizar el estudio, la categoría IV disminuyó y la categoría I aumentó de manera importante. Estos hallazgos evidencian que la anamnesis adecuada, el examen físico, el genograma y los exámenes básicos de genética, contribuyen a la detección de enfermedades genéticas, incluso en niveles de atención de baja complejidad en salud. Se evaluó, además, el grado de cumplimiento de las guías de manejo para síndrome de Down en estos pacientes, siendo inadecuado por cada ítem. El abordaje del paciente en situación de discapacidad requiere, entre otras cosas, la valoración y los estudios genéticos. El conocer la etiología permitirá mejor entendimiento y aceptación del paciente y su familia de su condición, planear estrategias de prevención y tratamiento adecuadas, y mejorar el proceso de toma de decisiones sobre reproducción en la familia.

Genetic diseases are a common cause of disability, but this fact is underestimated. Properly and opportune medical interventions on patients with these diseases are not enough yet. The aim of this study was to determine the prevalence of genetic disease in a disabled population from a Colombian rural area. Thirty five patients and their families with different chronic disabling conditions were evaluated. Each patient was assigned to one of five groups on the basis of the presence or absence of an underlying chronic medical condition and whether that condition had a genetic basis or susceptibility as follows: I category (monogenic diseases), II (chromosomal disorders), III (multifactorial diseases), IV (unknown etiology diseases or acquired disorders without genetic determinant), V (no preexisting chronic medical condition, no genetic disease basis). Once genetic evaluation was performed, the etiologic diagnoses were reclassified according those categories. Before genetic evaluation, the patients were categorized in the IV and II categories. After the genetic evaluation and genetics tests were done, the patients of IV category dropped while patients in I category raised. This demonstrates that right anamnesis, physical exam, complete family history tree and some basic genetics tests are required for proper diagnosis of genetic diseases, even in centers of primary care. We also asses the medical guidelines compliance for the Down syndrome in this population and this was unsatisfactory. Finally, we conclude that establishment of the genetic disease contributes to patients and the families in the understanding of their condition and also promotes better strategies of medical attention, according to the medical needs of this patients, including reproductive assessment.

Atenção em genética médica no sus: a experiência de um município de médio porte / Attention in medical genetics in the brazilian health system: the experience of a medium-sized municipality

Realizou-se estudo descritivo e exploratório da experiência em município de médio porte da implantação de ações na área da Genética, conjugando a análise dos documentos oficiais e de um questionário aplicado a 43 profissionais de nível superior da Estratégia Saúde da Família. Os dados obtidos foram analisados buscando obter respostas sobre como e por que foram realizadas determinadas estratégias de atenção à saúde na área da Genética Clínica e Comunitária. Tais ações foram classificadas em "educação permanente", "vigilância em saúde" e "ampliação do acesso à assistência". Os resultados revelaram que ainda é necessário estender as ações de educação permanente na área para profissionais da atenção primária, possibilitando assim promover a efetivação dessa porta de entrada do Sistema Único de Saúde para a área da Genética e o acesso a um cuidado integral em saúde.

We conducted a descriptive study on the experience of implementation of actions in the area of genetics in a medium-sized municipality, combining the analysis of official documents and a questionnaire administered to 43 university level professionals of the Family Health Strategy. The data were analyzed looking for answers about how and why certain health care strategies in the area of clinical and community genetics were performed. Such actions were classified as "continuing education", "health surveillance" and "enhanced access to care". The results showed that it is still necessary to extend the actions of continuing education in genetics for primary care professionals, promoting this gateway to the SUS also to the area of genetics, in order to allow full access to comprehensive health care.

Challenge of Personalized Medicine in the Genomic Era

"Personalized medicine," the goal of which is to provide better clinical care by applying patient's own genomic information to their health care is a global challenge for the 21st century "genomic era." This is especially true in Korea, where provisions for clinical genetic services are inadequate for the existing demand, let alone future demands. Genomics-based knowledge and tools make it possible to approach each patient as a unique biological individual, which has led to a paradigm-shift in medical practice, giving it more of a predictive focus as compared with current treatment oriented approach. With recent advancements in genomics, many genetic tests, such as susceptibility genetic tests, have been developed for both rare single gene diseases and more common multifactorial diseases. Indeed, genetic tests for presymtomatic individuals and genetic tests for drug response have become widely available, and personalized medicine will face the challenge of assisting patients who use such tests to make appropriate and wise use of genetic risk assessment. A major challenge of genomic medicine lies in understanding and communicating disease risk in order to facilitate and support patients and their families in making informed decisions. Establishment of a health care system with provisions for genetic counseling as an integral part of health care service, in addition to genomic literacy of health care providers, is vital to meet this growing challenge. Realization of the promise of personalized medicine in the era of genomics for improvement of health care is dependent on further development of next generation sequencing technology and affordable sequencing test costs. Also necessary will be policy development concerning the ethical, legal and social issues of genomic medicine and an educated and ready medical community with clinical practice guidelines for genetic counseling and genetic testing.

Clinical Genetics Education Program in Medical School: A Trial in Nippon Medical School / 医学教育

Advances in genetic medicine has rapidly been applied to clinical practice. However, many medical students have not studied biology or genetics in high school. There is little chance to think in Japan medical education about how to treat genetic information appropriately in the setting of clinical medicine. The timing and contents of a clinical genetics education program in medical school has hardly been discussed in Japan. This paper discusses the clinical genetics educationduring the medical-science and clinical-medicine stages at Nippon Medical School.<BR>1) An exercise on information gathering and role-play (for 180 minutes) about color vision deficiency were performed during the second-year molecular genetics course.<BR>2) A clinical genetics course (45 minutes 18 classes) in the fourth year was started in 2002 as a part of an integrated medical curriculum with courses classified by organ system.<BR>3) This clinical genetics course included systematic lectures for knowledge acquisition, lectures by patient support groups, exercises in drawing pedigrees, role-play, and discussions of ethical issues. Students evaluated this course favorably.<BR>4) Some topics in clinical genetics can be effectively presented at an early stage of medical education as part of an introduction to medicine. To maximize the educational effects and increase the possibility that students understand the importance of medical genetics, clinical genetics education in medical school will be performed after the student have grasped a basic understanding of diseases through lectures about clinical subjects.

Genetic counseling in Korean health care system

Unprecedented amount of genetic information being generated from the result of Human Genome Project (HGP) and advances in genetic research is already forcing changes in the paradigm of health and disease. The ultimate goal of genetic medicine is to use genetic information and technology to develop new ways of treatment or even prevention of the disease on an individual level for 'personalized medicine'. Genetics is playing an increasingly important role in the diagnosis, monitoring and management of common multifactorial diseases in addition to rare single-gene disorders. While wide range of genetic testing have provided benefits to patients and family, uncertainties surrounding test interpretation, the current lack of available medical options for the diseases, and risks for discrimination and social stigmatization may remain to be resolved. However an increasing number of genetic tests are becoming commercially available, including direct to consumer genetic testing, yet public is often unaware of their clinical and social implications. The personal nature of information generated by a genetic test, its power to affect major life decisions and family members, and its potential misuse raise important ethical considerations. Therefore appropriate genetic counseling is needed for patient to be informed with the benefits, limitations and risks of genetic tests, prior to informed consent for the tests. Physician also should be familiar with the legal and ethical issues involved in genetic testing to tell patients how well a particular genetic risk factor relates with likelihood of disease, and be able to provide appropriate genetic counseling. Genetic counseling become a mandatory requirement as global standard for many genetic testing such as prenatal diagnosis, presymtomatic DNA diagnostic tests and cancer susceptibility gene test for familial cancer syndrome. In oder to meet the challenge of genetic medicine of 21 century in korean health care system, professional education program and certification board for medical genetics specialist including non-MD genetic counselors should be addressed by medical society and regulatory policy of national health insurance reimbursement for genetic counseling to be in place to promote the implementation of clinical genetic service including genetic counseling for proper genetic testing.

A Questionnaire Study of Medical Students' Comprehension of Clinical Genetics: The Necessity of Education in Clinical Genetics in Medical School / 医学教育

Because of the rapid progress in genetic research, only a small part of what is known about clinical genetics is taught in medical schools. At Nippon Medical School a clinical genetics course for fourth-year students started in October 2002. In the present study, we used a questionnaire to investigate how well second-year medical school students understand clinical genetics. The results of the questionnaire suggested that many students are confused about basic concepts in clinical genetics, such as the differences between inherited disease and diseased caused by genetic disorders and between hereditary and chromosomal disorders and also suggested that education in clinical genetics is needed in medical schools. In the United States, guidelines for teaching genetics in medical schools have been established. However, in Japan, considering the lack of consensus about medical genetics terminology, to disseminate correct knowledge about clinical genetics, the present situation of medical genetics education in medical schools must be clarified, and various other measures, such as establishing what information should be taught, should be carried out.