Rare inherited kidney diseases: an evolving field in Nephrology / Doenças renais hereditárias raras: um campo em evolução na Nefrologia

Abstract There are more than 150 different rare genetic kidney diseases. They can be classified according to diagnostic findings as (i) disorders of growth and structure, (ii) glomerular diseases, (iii) tubular, and (iv) metabolic diseases. In recent years, there has been a shift of paradigm in this field. Molecular testing has become more accessible, our understanding of the underlying pathophysiologic mechanisms of these diseases has evolved, and new therapeutic strategies have become more available. Therefore, the role of nephrologists has progressively shifted from a mere spectator to an active player, part of a multidisciplinary team in the diagnosis and treatment of these disorders. This article provides an overview of the recent advances in rare hereditary kidney disorders by discussing the genetic aspects, clinical manifestations, diagnostic, and therapeutic approaches of some of these disorders, named familial focal and segmental glomerulosclerosis, tuberous sclerosis complex, Fabry nephropathy, and MYH-9 related disorder.

Resumo As doenças renais genéticas raras compreendem mais de 150 desordens. Elas podem ser classificadas segundo achados diagnósticos como (i) distúrbios do crescimento e estrutura, (ii) doenças glomerulares, (iii) tubulares e (iv) metabólicas. Nos últimos anos, houve uma mudança de paradigma nesse campo. Os testes moleculares tornaram-se mais acessíveis, nossa compreensão sobre os mecanismos fisiopatológicos subjacentes a essas doenças evoluiu e novas estratégias terapêuticas foram propostas. Portanto, o papel do nefrologista mudou progressivamente de mero espectador a participante ativo, parte de uma equipe multidisciplinar, no diagnóstico e tratamento desses distúrbios. O presente artigo oferece um panorama geral dos recentes avanços a respeito dos distúrbios renais hereditários raros, discutindo aspectos genéticos, manifestações clínicas e abordagens diagnósticas e terapêuticas de alguns desses distúrbios, mais especificamente a glomeruloesclerose segmentar e focal familiar, complexo da esclerose tuberosa, nefropatia de Fabry e doença relacionada ao MYH9.

Application value of whole exome sequencing in critically ill neonates with inherited diseases / 中国当代儿科杂志

OBJECTIVE@#To study the application value of whole exome sequencing (WES) in critically ill neonates with inherited diseases.@*METHODS@#A total of 66 critically ill neonates with suspected inherited diseases or unclear clinical diagnosis who were admitted to the neonatal intensive care unit were enrolled as subjects. The clinical data of the neonates were collected, and venous blood samples were collected from the neonates and their parents for WES. The clinical manifestations of the neonates were observed to search for related pathogenic gene mutations.@*RESULTS@#Among the 66 critically ill neonates with suspected inherited diseases or unclear clinical diagnosis (34 boys and 32 girls), 14 (21%) were found to have gene mutations by WES. One neonate had no gene mutation detected by WES but was highly suspected of pigment incontinence based on clinical manifestations, and multiplex ligation-dependent probe amplification detected a heterozygous deletion mutation in exons 4-10 of the IKBKG gene. Among the 15 neonates with gene mutations, 10 (67%) had pathogenic gene mutation, 1 (7%) was suspected of pathogenic gene mutation, and 4 (27%) had gene mutations with unknown significance. Among the 15 neonates, 13 underwent chromosome examination, and only 1 neonate was found to have chromosome abnormality.@*CONCLUSIONS@#Chromosome examination cannot be used as a diagnostic method for inherited diseases, and WES detection technology is an important tool to find inherited diseases in critically ill neonates with suspected inherited diseases or unclear clinical diagnosis; however WES technology has some limitation and it is thus necessary to combine with other sequencing methods to achieve an early diagnosis.

How diseases became "genetic" / Como as doenças se tornaram "genéticas"

Abstract This article examines the origins of the term "genetic disease." In the late 19 and early 20th century, an earlier idea that diseases that occur in families reflect a vague familiar "predisposition" was replaced by the view that such diseases have specific causes, while Mendelian genetics provided then clues to the patterns of their transmission. The genetictisation of inborn pathologies took a decisive turn with the redefinition, in 1959, of Down syndrome as a chromosomal anomaly, then the development of tests for the diagnosis of other hereditary pathologies. At that time, geneticists distinguished "hereditary" diseases that run in families, from "genetic" conditions that are the result of new mutations during the production of egg and sperm cells. In the latter case, the inborn impairment is produced by an anomaly in the genetic material of the cell, but is not hereditary, because it is not transmitted from one or both parents. In the late 20th and early 21st century, new genomic technologies blurred the distinction between hereditary and genetic impairments, extended the concept of genetic disease, and modified the experience of people living with such a disease.

Resumo O presente artigo tem o objetivo de examinar as origens do termo "doença genética. No final do século XIX e início do XX, a vaga ideia que a doença manifesta entre familiares refletia uma "predisposição" familiar, foi substituída pela visão que essas doenças possuem causas específicas, enquanto a genética mendeliana forneceu as pistas para os padrões de transmissão da doença. A genética das patologias congênitas deu uma guinada decisiva, em 1959, com a redefinição da Síndrome de Down como uma anomalia cromossômica e, depois, com o desenvolvimento de testes para o diagnóstico de outras patologias hereditárias. Naquela época, os geneticistas distinguiam doenças "hereditárias" como aquelas que acometiam os elementos de uma família, de condições "genéticas" que são o resultado de novas mutações ocorridas durante a produção dos óvulos e espermatozoides. Neste último caso, a deficiência inata é causada por uma anomalia do material genético da célula, porque não é transmitida por qualquer um ou ambos os pais. No final do século XX e início do XXI, as novas tecnologias genômicas obscureceram a distinção entre deficiências hereditária e a genética, estenderam o conceito da doença genética e modificaram a experiência das pessoas que vivem com esse tipo de doença.

Doenças genéticas raras com abordagem qualitativa: revisão integrativa da literatura nacional e internacional / A qualitative approach to rare genetic diseases: an integrative review of the national and international literature

Resumo Atualmente, há entre seis e oito mil adoecimentos catalogados por doenças raras, sendo que 80% são de origem genética e entre os estudos sobressaem os de natureza quantitativa e biomédica. Objetivou-se identificar e descrever as características dos estudos científicos, no Brasil e internacionalmente, com abordagem qualitativa, acerca das doenças genéticas raras publicados em bases indexadas na área da saúde e das ciências sociais. Utilizaram-se as bases de dados Scielo, Lilacs, Medline, PubMed, BDENF, Web of Science, Scopus e CINAHL, com os descritores: "Qualitative Research" e "Rare Disease", entre 2013-2018. Foram selecionados 171 artigos, classificados por ano, país, idioma, tipo de doença rara, estratégia de coleta de dados, área de conhecimento e tema. As produções revelam a pertinência dos estudos qualitativos sobre doença genética rara no seu potencial para subsidiar a organização, a tomada de decisões e a formação em saúde, de maneira que respondam às necessidades sociais e individuais da comunidade. É importante, todavia, desenvolver mais estudos, principalmente brasileiros, que abordem as condições genéticas raras, relevando as vivências e os afetamentos nas interações pessoais, familiares, profissionais e organizacionais perante os modos próprios e efetivos de cuidar.

Abstract There are currently between six and eight thousand illnesses classified as rare diseases, 80% of which are of genetic origin and among the studies those of a quantitative and biomedical nature stand out. The objective of this study was to identify and describe the characteristics of scientific studies in Brazil and worldwide using a qualitative approach on rare genetic diseases published in indexed databases in the area of health and social sciences. The Scielo, Lilacs, Medline, PubMed, BDENF, Web of Science, Scopus and CINAHL databases were researched between 2013-2018 using the key words "Qualitative Research" and "Rare Disease." A total of 171 articles, classified by year, country, language, rare disease type, data collection strategy, knowledge area and theme were selected. The texts reveal the relevance of qualitative studies on rare genetic diseases in their ability to support organization, decision-making and health training in a way that responds to the social and individual needs of the community. It is important, however, to conduct further studies, especially within Brazil, that address rare genetic conditions, revealing the experiences and how they affect the personal, family, professional and organizational interactions in terms of the proper and effective modes of care.

Diagnóstico molecular de enfermedades genéticas: del diagnóstico genético al diagnóstico genómico con la secuenciación masiva / Molecular diagnosis of genetic diseases: from genetic to genomic diagnosis using next generation sequencing

En la actualidad se conocen 8.000 enfermedades genéticas monogénicas. La mayoría de ellas son heterogéneas, por lo que el diagnóstico molecular por técnicas convencionales de secuenciación suele ser largo y costoso debido al gran número de genes implicados. El tiempo estimado para el diagnóstico molecular se encuentra entre 1 y 10 años, y este retraso impide que los pacientes reciban medidas terapéuticas y de rehabilitación específicas, que sus familiares entren en programas preventivos y que reciban asesoramiento genético. La secuenciación masiva está cambiando el modelo de diagnóstico molecular de los afectos, sin embargo, los médicos y profesionales de la salud se enfrentan al dilema de la selección del método más eficiente, con el menor coste sanitario y con la mayor precisión de sus resultados. El objetivo de este trabajo es revisar la tecnología de secuenciación masiva y definir las ventajas y los problemas en su utilización.

Currently 8000 monogenic genetic diseases are known. Most of them are heterogeneous, so their molecular diagnosis by conventional sequencing techniques is labour intensive and time consuming due to the large number of genes involved. The estimated time is between 1 and 10 years for molecular diagnosis and this delay prevents patients from receiving therapy and rehabilitation measures, and their families from entering prevention programs and being given genetic counselling. Next generation sequencing (NGS) is changing the model of molecular diagnosis of patients; however, doctors and health professionals are faced with the dilemma of choosing the most efficient method, with lower health care costs and the most accurate results. The aim of this paper is to review the NGS technology and define the advantages and problems in the use of this technology.

EXPERIENCE WITH THE BRAZILIAN NETWORK FOR STUDIES IN REPRODUCTIVE AND PERINATAL HEALTH: THE POWER OF COLLABORATION IN POSTGRADUATE PROGRAMS / EXPERIÊNCIA COM A REDE BRASILEIRA DE ESTUDOS EM SAÚDE REPRODUTIVA E PERINATAL: O PODER DA COLABORAÇÃO NA PÓS-GRADUAÇÃO

The scientific collaboration in networks may be developed among countries, academic institutions and among peer researchers. Once established, they contribute for knowledge dissemination and a strong structure for research in health. Several advantages are attributed to working in networks: the inclusion of a higher number of subjects in the studies; generation of stronger evidence with a higher representativeness of the population (secondary generalization and external validity); higher likelihood of articles derived from these studies to be accepted in high impact journals with a wide coverage; a higher likelihood of obtaining budgets for sponsorship; easier data collection on rare conditions; inclusions of subjects from different ethnic groups and cultures, among others. In Brazil, the Brazilian Network for Studies on Reproductive and Perinatal Health was created in 2008 with the initial purpose of developing a national network of scientific cooperation for the surveillance of severe maternal morbidity. Since the establishment of this Network, five studies were developed, some of them already finished and others almost being completed, and two new ones being implemented. Results of the activities in this Network have been very productive and with a positive impact on not only the Postgraduate Program of Obstetrics and Gynecology from the University of Campinas, its coordinating center, but also on other participating centers. A considerable number of scientific articles was published, master´s dissertations and PhD theses were presented, and post-doctorate programs were performed, including students from several areas of health, from distinct regions and from several institutions of the whole country. This represents a high social impact taking into account the relevance of the studied topics for the country.

As colaborações científicas em rede podem ocorrer entre países, instituições acadêmicas e entre pares de pesquisadores e, uma vez estabelecidas, contribuem para a disseminação do conhecimento e estruturação da pesquisa em saúde. Diversas vantagens são atribuídas ao trabalho em rede como: a inclusão de maior número de participantes nos estudos; gerar evidências mais fortes e com maior representatividade da população (generalização secundária e validade externa); maior facilidade das publicações oriundas dos estudos serem aceitas em periódicos de impacto e abrangência; maior probabilidade de obtenção de verbas para financiamento; maior facilidade na coleta de dados sobre condições raras; inclusão de participantes de diferentes grupos étnicos e culturas, entre outras. No Brasil a Rede Brasileira de Estudos em Saúde Reprodutiva e Perinatal foi criada em 2008 com o objetivo inicial de desenvolver rede nacional de cooperação científica para vigilância da morbidade materna grave. Desde sua formação, cinco estudos foram desenvolvidos, alguns já encerrados e outros em fase de finalização, com outros dois em fase final de implantação. Os resultados das atividades desta Rede têm sido bastante produtivos e impactaram positivamente não apenas no Programa de Pós-Graduação em Tocoginecologia da Universidade Estadual de Campinas, seu centro coordenador, mas também o de outros centros participantes, uma vez que expressivo número de artigos científicos foi publicado, mestrados e doutorados foram defendidos e pós-doutorados finalizados, de alunos de diversas áreas da saúde, de diferentes regiões e de várias instituições de todo o país, com alto impacto social dada a relevância dos temas estudados para o país.

Aplicación de la genética de poblaciones en el ámbito de la medicina / Application of population genetics in the field of medicine

Las poblaciones humanas obedecen a los mismos supuestos evolutivos que el resto de los organismos, aunque mezclados con elementos sociales y culturales que pueden promover la expresión de ciertas enfermedades en grupos étnicos específicos, causadas principalmente por la frecuente endogamia. En este trabajo se analiza el principio de Hardy-Weinberg desde un enfoque médico, social y biológico, para entender los procesos evolutivos que dan lugar a las enfermedades autosómicas recesivas. A manera de conclusión se puede señalar que la incidencia de estas enfermedades está inversamente relacionada con los niveles de la variabilidad genética en las poblaciones, variabilidad que depende de eventos de colonización, recolonización y migración, así como de convenciones sociales como el racismo, la estratificación social y la segregación.

Human populations follow the same evolutionary principles as other organisms, although mixed with social and cultural elements, which can result in a high prevalence of certain diseases within specific ethnic groups. In this work, the Hardy-Weinberg principle is analyzed from a medical, social and biological viewpoint to understand the evolutionary processes of autosomal recessive diseases. It can be concluded that the incidence of these diseases is inversely related to the levels of genetic variability within populations, which depends on colonization, recolonization and migration events, as well as on social conventions such as racism, social stratification and segregation.

Power comparison between population-based case–control studies and family-based transmission–disequilibrium tests: An empirical study.

BACKGROUND: There are two major classes of genetic association analyses: population based and family based. Population-based case–control studies have been the method of choice due to the ease of data collection. However, population stratification is one of the major limitations of case–control studies, while family-based studies are protected against stratification. In this study, we carry out extensive simulations under different disease models (both Mendelian as well as complex) to evaluate the relative powers of the two approaches in detecting association. MATERIALS AND METHODS: The power comparisons are based on a case–control design comprising 200 cases and 200 controls versus a Transmission Disequilibrium Test (TDT) or Pedigree Disequilibrium Test (PDT) design with 200 informative trios. We perform the allele-level test for case–control studies, which is based on the difference of allele frequencies at a single nucleotide polymorphism (SNP) between unrelated cases and controls. The TDT and the PDT are based on preferential allelic transmissions at a SNP from heterozygous parents to the affected offspring. We considered five disease modes of inheritance: (i) recessive with complete penetrance (ii) dominant with complete penetrance and (iii), (iv) and (v) complex diseases with varying levels of penetrances and phenocopies. RESULTS: We find that while the TDT/PDT design with 200 informative trios is in general more powerful than a case–control design with 200 cases and 200 controls (except when the heterozygosity at the marker locus is high), it may be necessary to sample a very large number of trios to obtain the requisite number of informative families. CONCLUSION: The current study provides insights into power comparisons between population-based and family-based association studies.

Aconselhamento genético: [revisão] / Genetic counseling: [review]

OBJETIVO: Esta revisão sobre aconselhamento genético (AG) teve o objetivo de mostrar os conceitos atuais e os princípios filosóficos e éticos aceitos na grande maioria dos países e recomendados pela Organização Mundial da Saúde, as fases do processo, seus resultados e o impacto psicológico de uma doença genética em uma família. FONTES DOS DADOS: Os conceitos apresentados são baseados em uma síntese histórica da literatura sobre AG desde a década de 1930 até o momento atual, sendo que os artigos citados representam os principais trabalhos publicados e que hoje fundamentam a teoria e a prática do AG. SÍNTESE DOS DADOS: O AG modernamente é definido como um processo de comunicação que trata dos problemas humanos relacionados à ocorrência de uma doença genética em uma família. É fundamental que os profissionais da saúde conheçam os aspectos psicológicos desencadeados pela doença genética e como estes aspectos podem ser manejados. Vivemos ainda na genética humana e médica uma fase de predomínio dos aspectos técnicos e científicos e de pouca ênfase no estudo das reações emocionais e dos processos de adaptação das pessoas a estas doenças, o que leva ao baixo entendimento dos clientes sobre os fatos ocorridos, com conseqüências negativas sobre a vida familiar e para a sociedade. CONCLUSÕES: Conclui-se pela necessidade de que as famílias com doenças genéticas sejam encaminhadas para AG e que os profissionais desta área invistam mais na humanização do atendimento, desenvolvendo mais as técnicas do AG psicológico não-diretivo.

OBJECTIVE: The objective of this review of genetic counseling (GC) is to describe the current concepts and philosophical and ethical principles accepted by the great majority of countries and recommended by the World Health Organization, the stages of the process, its results and the psychological impact that a genetic disease has on a family. SOURCES: The concepts presented are based on an historical synthesis of the literature on GC since the 1930s until today, and the articles cited represent the most important research published which today provides the foundation for the theory and practice of GC. SUMMARY OF THE FINDINGS: The modern definition of GC is a process of communication that deals with the human problems related with the occurrence of a genetic disease in a family. It is of fundamental importance that health professionals are aware of the psychological aspects triggered by genetic diseases and the ways in which these can be managed. In the field of human and medical genetics we are still living in a phase in which technical and scientific aspects predominate, with little emphasis on the study of emotional reactions and people's processes of adaptation to these diseases, which leads to clients having a low level of understanding of the events that have taken place, with negative consequences for family life and for society. CONCLUSIONS: The review concludes by discussing the need to refer families with genetic diseases for GC and the need for professionals working in this area to invest more in humanizing care and developing non-directive psychological GC techniques.

A theoretical treatment of interval mapping of a disease gene using transmission disequilibrium tests.

The genetic basis of the transmission disequilibrium test (TDT) for two-marker loci is explored from first principles. In this case, parents doubly heterozygous for a given haplotype at the pair of marker loci that are each in linkage disequilibrium with the disease gene with the further possibility of a second-order linkage disequilibrium are considered. The number of times such parents transmit the given haplotype to their affected offspring is counted and compared with the frequencies of haplotypes that are not transmitted. This is done separately for the coupling and repulsion phases of doubly heterozygous genotypes. Expectations of the counts for each of the sixteen cells possible with four-marker gametic types (transmitted vs not transmitted) are derived. Based on a test of symmetry in a square 4 x 4 contingency table, chi-square tests are proposed for the null hypothesis of no linkage between the markers and the disease gene. The power of the tests is discussed in terms of the corresponding non-centrality parameters for the alternative hypothesis that both the markers are linked with the disease locus. The results indicate that the power increases with the decrease in recombination probability and that it is higher for a lower frequency of the disease gene. Taking a pair of markers in an interval for exploring the linkage with the disease gene seems to be more informative than the single-marker case since the values of the non-centrality parameters tend to be consistently higher than their counterparts in the single-marker case. Limitations of the proposed test are also discussed.

Trombofilias hereditárias e repercussões fetais e perinatais: o que há de novo? / Inherited thrombophilias and fetal and perinatal outcome: what is new?

As trombofilias hereditárias caracterizam-se por alterações da coagulação associadas com predisposição à trombose e são relacionadas a diversas complicações fetais e perinatais, tais como o aborto habitual, as perdas fetais tardias, a restrição de crescimento fetal (RCF)e, mais recentemente, com o parto pré-termo. Entre as trombofilias destacam-se: a mutação do fator V (fator V Leiden) e do fator II (protrombina) e as deficiências das proteínas S e C e da antitrombina. Em pacientes com perdas fetais de repetição, o tratamento com heparina tem sido utilizado, porém, ainda são necessários mais estudos para se comprovar a real eficácia desta terapêutica.

Genetic polymorphisms and implications for human diseases.

After the sequencing of the human genome is done, enormous genomic information and high-throughput profiling technologies are used. Increased attention has been paid to applying this knowledge to get better understanding of inherited diseases and complex disorders. Single nucleotide polymorphisms (SNPs) are DNA sequence variations that occur when a single nucleotide in the genome sequence is altered SNPs are an important tool for the study of the human genome. Application of SNPs analysis to human disease permits exploration of the influence of genetic polymorphisms on disease susceptibility, drug sensitivity/resistance, and ultimately health care. Databases of SNPs provide a powerful resource for association studies that try to establish a relationship between a phenotype and regions of the genome. Genomic approaches have garnered so much attention and investment because they offer the potential to provide better understanding of genetic factors in human health and disease, as well as more-precise definitions of the non-genetic factors involved.

Laminopathies: multiple disorders arising from defects in nuclear architecture.

Lamins are the major structural proteins of the nucleus in an animal cell. In addition to being essential for nuclear integrity and assembly, lamins are involved in the organization of nuclear processes such as DNA replication, transcription and repair. Mutations in the human lamin A gene lead to highly debilitating genetic disorders that primarily affect muscle, adipose, bone or neuronal tissues and also cause premature ageing syndromes. Mutant lamins alter nuclear integrity and hinder signalling pathways involved in muscle differentiation and adipocyte differentiation, suggesting tissue-specific roles for lamins. Furthermore, cells expressing mutant lamins are impaired in their response to DNA damaging agents. Recent reports indicate that certain lamin mutations act in a dominant negative manner to cause nuclear defects and cellular toxicity, and suggest a possible role for aberrant lamins in normal ageing processes.

Alterações ecocardiográficas em doenças genéticas / Echocardiographic features of genetic diseases

A identificação ecocardiográfica de cardiopatias em indivíduos com alterações genéticas e em familiares pode representar um avanço muito grande no manuseio dessas anomalias. Apresentamos de maneira resumida, as mais importantes doenças genéticas associadas a alterações cardiovasculares morfológicas e/ou funcionais, e suas correspondentes alterações ecocardiográficas. Em seguida discutimos sobre o valor do método no rastreamento de familiares com doenças genéticas

Enfermedades genéticas que afectan la cavidad bucal: revisión de la literatura / Genetic diseases affecting the oral cavity: review of the literature

En el presente artículo se hace referencia a síndromes y enfermedades sistémicas involucradas en la cronología de la erupcion dentaria, afeccion de los maxilares y en general con manifestaciones a nivel de la cavidad bucal. La lista es excesiva, y por lo tanto no se pueden mencionar todos los isndromes y enfermedades sistémicas comprometidas, motivo por el cual nos limitaremos a algunas de las entidades más representativas del probelma como son: querubismo, displasia cleidocraneal, disostosis craneofacial, Síndrome de teacher Collins, Síndrome de Pierre Robin, Síndrome de Hollermann Streiff, osteopetrosis, osteogénesis imperfecta, Síndrome de Albright, Síndrome de Ellis - Van Creveld, Síndrome de Down, Síndrome de múltiples carcinomas basocelulares nevoides y quistes de los maxilares, Síndrome de Marfan. Para este estudio nos hemos basado en la clasificación de las enfermedades bucodentales de origen genético que hace la Clasificación Internacional de Enfermedades aplicadas a la odontología y estomatología (CIE -AO), Organización Panamericana de la Salud, 1985. El conocimiento de la existencia de estas patologías reviste gran importancia pues requieren de varios cuidados y remisión a especialistas adecuados. Con este artículo se pretende hacer un aporte en el reconocimiento de enfermedades que aunque no están relacionadas directamente con el odontólogo, éste debe conocer para su correcto manejo