RESUMEN
Spinocerebellar ataxia type 7 (SCA7) is a rare genetic disease characterized by progressive cerebellar syndrome and macular degeneration. In a previous study, we clinically and genetically characterized a group of Mexican patients, which represented one of the largest cohorts of SCA7 patients worldwide and demonstrated that all patients had a unique genetic origin. Our laboratory developed a program for the diagnosis, medical care, and long-term follow-up of these patients living in Veracruz State, and in this report, we present an update to this research, covering 2013 to 2024. So far, we identified 172 SCA7 carriers, with a few cases outside Veracruz, and our data support that the length of the CAG repeat tract mainly determines disease severity and life expectancy, and accordingly, we define three different phenotypes, early-onset (EO), classical-onset (CO), and late-onset (LO), with EO patients showing the lowest life expectancy. Furthermore, we found that parental transmission of mutant alleles leads to increased CAG repeat instability, compared to maternal ones. Interestingly, a haplotype analysis revealed that patients outside Veracruz may have different genetic origins. In conclusion, longitudinal observations of SCA7 patients provide insight into the natural history of SCA7 and help to design strategies for diagnosis, genetic counseling, physical rehabilitation, and therapeutic alternatives.
Asunto(s)
Enfermedades Raras , Ataxias Espinocerebelosas , Humanos , Ataxias Espinocerebelosas/genética , Ataxias Espinocerebelosas/epidemiología , Ataxias Espinocerebelosas/terapia , Ataxias Espinocerebelosas/diagnóstico , México/epidemiología , Femenino , Masculino , Enfermedades Raras/genética , Enfermedades Raras/terapia , Enfermedades Raras/diagnóstico , Enfermedades Raras/epidemiología , Adulto , Persona de Mediana Edad , Fenotipo , Expansión de Repetición de Trinucleótido , Haplotipos , Edad de InicioRESUMEN
The present study aimed to compare the prevalence of oral problems between individuals with rare genetic diseases that affect skeletal development and individuals without rare diseases. A cross-sectional study was conducted with 210 individuals between two and fifty-four years of age: 105 with rare genetic diseases (27 with mucopolysaccharidosis [MPS] and 78 with osteogenesis imperfecta [OI]) and 105 without rare diseases. The rare genetic disease group was recruited from hospital units that provide care for patients with MPS and OI in five states of Brazil, and the other group was recruited from the same location. The participants were examined with regards to malocclusion, dental anomalies, dental caries, and gingivitis. A questionnaire was administered addressing individual, sociodemographic, and behavioral characteristics as well as dental history. A descriptive analysis was performed, followed by unadjusted and adjusted binary logistic regression analyses. The mean age was 14.1 ± 12.2 years. Individuals with a rare disease were 12.9-fold more likely to have some type of oral problem (95% CI: 3.7-44.7) compared to the group without rare diseases. The prevalence of oral problems was higher among Brazilians with MPS and OI compared to normotypical individuals.
Asunto(s)
Osteogénesis Imperfecta , Enfermedades Raras , Humanos , Brasil/epidemiología , Masculino , Femenino , Adulto , Estudios Transversales , Niño , Preescolar , Adolescente , Adulto Joven , Persona de Mediana Edad , Osteogénesis Imperfecta/epidemiología , Osteogénesis Imperfecta/genética , Prevalencia , Enfermedades Raras/epidemiología , Enfermedades Raras/genética , Mucopolisacaridosis/epidemiología , Mucopolisacaridosis/genética , Enfermedades de la Boca/epidemiología , Maloclusión/epidemiología , Caries Dental/epidemiologíaRESUMEN
Rare diseases are characterized by low prevalence and high complexity, affecting millions globally. Although technologies like massive sequencing improve diagnose, therapeutic options remain largely symptomatic or palliative, with few curative treatments approved. In the context of rare diseases, especially genetic neurodevelopmental disorders, therapy development faces obstacles such as phenotypic variability, diverse molecular mechanisms, and complexities in assessing neurodevelopment in natural history and clinical trials. Current strategies include drug repositioning, biomarker development, and a multilateral approach in seeking solutions, offering hope. This work reviews various strategies in developing therapies, from gene therapy and epigenetic therapies to identifying biological targets.
Las enfermedades raras, caracterizadas por su baja prevalencia y alta complejidad, afectan a millones de personas globalmente. Los avances en tecnologías como la secuenciación masiva mejoran nuestra capacidad de diagnóstico, aunque el manejo terapéutico sigue siendo mayoritariamente sintomático o paliativo, con muy escasos tratamientos curativos aprobados. En el contexto de las enfermedades raras, especialmente los trastornos del neurodesarrollo de base genética, el desarrollo de terapias se enfrenta a múltiples retos, como la alta variabilidad fenotípica, los diversos mecanismos moleculares y biológicos subyacentes y las dificultades en la evaluación del neurodesarrollo tanto en la historia natural como en los ensayos clínicos. En la actualidad, estrategias como el reposicionamiento de fármacos, el desarrollo de biomarcadores y un enfoque multilateral en la búsqueda de soluciones amplían las posibilidades y ofrecen un escenario esperanzador. Este trabajo revisa diversas estrategias en el desarrollo de terapias, desde las terapias génicas y epigenéticas hasta la intervención en potenciales dianas biológicas.
Asunto(s)
Terapia Genética , Enfermedades Raras , Humanos , Enfermedades Raras/terapia , Enfermedades Raras/genética , Terapia Genética/métodos , Reposicionamiento de Medicamentos , Biomarcadores/análisisRESUMEN
Exome and genome sequencing (ES/GS) are routinely used for the diagnosis of genetic diseases in developed countries. However, their implementation is limited in countries from Latin America. We aimed to describe the results of GS in patients with suspected rare genetic diseases in Colombia. We studied 501 patients from 22 healthcare sites from January to December 2022. GS was performed in the index cases using dried blood spots on filtercards. Ancestry analysis was performed under iAdmix. Multiomic testing was performed when needed (biomarker, enzymatic activity, RNA-seq). All tests were performed at an accredited genetic laboratory. Ethnicity prediction data confirmed that 401 patients (80%) were mainly of Amerindian origin. A genetic diagnosis was established for 142 patients with a 28.3% diagnostic yield. The highest diagnostic yield was achieved for pathologies with a metabolic component and syndromic disorders (p < 0.001). Young children had a median of 1 year of diagnostic odyssey, while the median time for adults was significantly longer (15 years). Patients with genetic syndromes have spent more than 75% of their life without a diagnosis, while for patients with neurologic and neuromuscular diseases, the time of the diagnostic odyssey tended to decrease with age. Previous testing, specifically karyotyping or chromosomal microarray were significantly associated with a longer time to reach a definitive diagnosis (p < 0.01). Furthermore, one out of five patients that had an ES before could be diagnosed by GS. The Colombian genome project is the first Latin American study reporting the experience of systematic use of diagnostic GS in rare diseases.
Asunto(s)
Enfermedades Raras , Secuenciación Completa del Genoma , Humanos , Colombia , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Adulto , Masculino , Femenino , Niño , Secuenciación Completa del Genoma/normas , Adolescente , Preescolar , Pruebas Genéticas/métodos , Pruebas Genéticas/normas , Persona de Mediana Edad , LactanteRESUMEN
Rare diseases affect millions of people worldwide, and most have a genetic etiology. The incorporation of next-generation sequencing into clinical settings, particularly exome and genome sequencing, has resulted in an unprecedented improvement in diagnosis and discovery in the past decade. Nevertheless, these tools are unavailable in many countries, increasing health care gaps between high- and low-and-middle-income countries and prolonging the "diagnostic odyssey" for patients. To advance genomic diagnoses in a setting of limited genomic resources, we developed DECIPHERD, an undiagnosed diseases program in Chile. DECIPHERD was implemented in two phases: training and local development. The training phase relied on international collaboration with Baylor College of Medicine, and the local development was structured as a hybrid model, where clinical and bioinformatics analysis were performed in-house and sequencing outsourced abroad, due to lack of high-throughput equipment in Chile. We describe the implementation process and findings of the first 103 patients. They had heterogeneous phenotypes, including congenital anomalies, intellectual disabilities and/or immune system dysfunction. Patients underwent clinical exome or research exome sequencing, as solo cases or with parents using a trio design. We identified pathogenic, likely pathogenic or variants of unknown significance in genes related to the patients´ phenotypes in 47 (45.6%) of them. Half were de novo informative variants, and half of the identified variants have not been previously reported in public databases. DECIPHERD ended the diagnostic odyssey for many participants. This hybrid strategy may be useful for settings of similarly limited genomic resources and lead to discoveries in understudied populations.
Asunto(s)
Fenotipo , Enfermedades Raras , Humanos , Chile , Enfermedades Raras/genética , Enfermedades Raras/diagnóstico , Masculino , Femenino , Niño , Enfermedades no Diagnosticadas/genética , Enfermedades no Diagnosticadas/diagnóstico , Enfermedades no Diagnosticadas/epidemiología , Secuenciación del Exoma/métodos , Preescolar , Pruebas Genéticas/métodos , AdolescenteRESUMEN
INTRODUCTION: The Brazilian Policy for Comprehensive Care for People with Rare Diseases (BPCCPRD) was published in 2014, accrediting several reference centers and incorporating many genetic tests for the diagnosis of rare diseases (RDs). The Brazilian Network of Rare Diseases (RARAS) comprises more than 40 institutions that offer diagnosis and treatment for RDs in Brazil. This network includes Reference Services for Rare Diseases (RDRS), Reference Services for Newborn Screening (NSRS), and University Hospitals distributed in all Brazilian regions. OBJECTIVE: The aim of the study was to map the availability and distribution of the BPCCPRD diagnostic procedures in the Brazilian Unified Health System through RARAS. METHOD: Data were collected through a questionnaire on the Research Electronic Data Capture platform, with 22 questions regarding the availability of procedures. Thirty-seven coordinators from RARAS participating centers received the questionnaire link for participation by email from August/2020 to March/2021. All participating institutions ethically approved this project. RESULTS: Of the 37 institutions, 23 (62.16%) offered cytogenetic tests, 20 (54.05%) offered molecular procedures, and 22 (59.46%) offered inborn errors of metabolism diagnostic tests. The Southern blot analysis, enzyme assays on cultured tissue and urinary organic acid tests had the highest outsourcing rate. On the other hand, the procedures most frequently performed on-site were bone marrow karyotype and long-term cultured karyotype. It was observed that 10 of the 37 centers (27%) did not provide access to investigated procedures (on-site or outsourced). The North and Midwest regions stood out in terms of the unavailability of such techniques in at least 40% of the evaluated institutions. DISCUSSION AND CONCLUSION: This study reveals large discrepancies in the supply of diagnostic procedures in the Brazilian territory. Moreover, there is a broad collaboration between services through the outsourcing of multiple diagnostic techniques to address this issue. Finally, this work corroborates the importance of mapping services for the diagnosis and treatment of individuals with RDs to propose actions for the better supply and distribution of these procedures.
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Pruebas Genéticas , Enfermedades Raras , Recién Nacido , Humanos , Brasil , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Encuestas y Cuestionarios , Tamizaje NeonatalRESUMEN
Early diagnosis of genetic rare diseases is an unmet need in Brazil, where an estimated 10-13 million people live with these conditions. Increased use of chromosome microarray assays, exome sequencing, and whole genome sequencing as first-tier testing techniques in suitable indications can shorten the diagnostic odyssey, eliminate unnecessary tests, procedures, and treatments, and lower healthcare expenditures. A selected panel of Brazilian experts in fields related to rare diseases was provided with a series of relevant questions to address before a multi-day conference. Within this conference, each narrative was discussed and edited through numerous rounds of discussion until agreement was achieved. The widespread adoption of exome sequencing and whole genome sequencing in Brazil is limited by various factors: cost and lack of funding, reimbursement, awareness and education, specialist shortages, and policy issues. To reduce the burden of rare diseases and increase early diagnosis, the Brazilian healthcare authorities/government must address the barriers to equitable access to early diagnostic methods for these conditions. Recommendations are provided, including broadening approved testing indications, increasing awareness and education efforts, increasing specialist training opportunities, and ensuring sufficient funding for genetic testing.
Asunto(s)
Pruebas Genéticas , Enfermedades Raras , Humanos , Secuenciación del Exoma , Brasil , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Secuenciación Completa del GenomaAsunto(s)
Exoma , Enfermedades Raras , Brasil , Humanos , Enfermedades Raras/genética , Análisis de Secuencia de ADNRESUMEN
Genomic studies may generate massive amounts of data, bringing interpretation challenges. Efforts for the differentiation of benign and pathogenic variants gain importance. In this article, we used segregation analysis and other molecular data to reclassify to benign or likely benign several rare clinically curated variants of autosomal dominant inheritance from a cohort of 500 Brazilian patients with rare diseases. This study included only symptomatic patients who had undergone molecular investigation with exome sequencing for suspected diseases of genetic etiology. Variants clinically suspected as the causative etiology and harbored by genes associated with highly-penetrant conditions of autosomal dominant inheritance underwent Sanger confirmation in the proband and inheritance pattern determination because a "de novo" event was expected. Among all 327 variants studied, 321 variants were inherited from asymptomatic parents. Considering segregation analysis, we have reclassified 51 rare variants as benign and 211 as likely benign. In our study, the inheritance of a highly penetrant variant expected to be de novo for pathogenicity assumption was considered as a non-segregation and, therefore, a key step for benign or likely benign classification. Studies like ours may help to identify rare benign variants and improve the correct interpretation of genetic findings.
Asunto(s)
Padres , Enfermedades Raras , Brasil , Humanos , Mutación , Linaje , Enfermedades Raras/genética , Secuenciación del ExomaRESUMEN
The Brazilian Policy of Comprehensive Care for People with Rare Diseases (BPCCPRD) was established by the Ministry of Health to reduce morbidity and mortality and improve the quality of life of people with rare diseases (RD). Several laboratory tests, most using molecular genetic technologies, have been incorporated by the Brazilian Public Health System, and 18 specialised centres have so far been established at university hospitals (UH) in the capitals of the Southern, Southeastern and Northeastern regions. However, whether the available human and technological resources in these services are appropriate and sufficient to achieve the goals of care established by the BPCCPRD is unknown. Despite great advances in diagnosis, especially due to new technologies and the recent structuring of clinical assessment of RD in Brazil, epidemiological data are lacking and when available, restricted to specific disorders. This position paper summarises the performance of a nationally representative survey on epidemiology, clinical status, and diagnostic and therapeutic resources employed for individuals with genetic and non-genetic RD in Brazil. The Brazilian Rare Disease Network (BRDN) is under development, comprising 40 institutions, including 18 UH, 17 Rare Diseases Reference Services and five Newborn Screening Reference Services. A retrospective study will be initially conducted, followed by a prospective study. The data collection instrument will use a standard protocol with sociodemographic data and clinical and diagnostic aspects according to international ontology. This great collaborative network is the first initiative of a large epidemiological data collection of RD in Latin America, and the results will increase the knowledge of RD in Brazil and help health managers to improve national public policy on RD in Brazil.
Asunto(s)
Calidad de Vida , Enfermedades Raras , Brasil/epidemiología , Humanos , Recién Nacido , Estudios Prospectivos , Enfermedades Raras/genética , Estudios RetrospectivosRESUMEN
BACKGROUND: Rare diseases are pathologies that affect less than 1 in 2000 people. They are difficult to diagnose due to their low frequency and their often highly heterogeneous symptoms. Rare diseases have in general a high impact on the quality of life and life expectancy of patients, which are in general children or young people. The advent of high-throughput sequencing techniques has improved diagnosis in several different areas, from pediatrics, achieving a diagnostic rate of 41% with whole genome sequencing (WGS) and 36% with whole exome sequencing, to neurology, achieving a diagnostic rate between 47 and 48.5% with WGS. This evidence has encouraged our group to pursue a molecular diagnosis using WGS for this and several other patients with rare diseases. RESULTS: We used whole genome sequencing to achieve a molecular diagnosis of a 7-year-old girl with a severe panvascular artery disease that remained for several years undiagnosed. We found a frameshift variant in one copy and a large deletion involving two exons in the other copy of a gene called YY1AP1. This gene is related to Grange syndrome, a recessive rare disease, whose symptoms include stenosis or occlusion of multiple arteries, congenital heart defects, brachydactyly, syndactyly, bone fragility, and learning disabilities. Bioinformatic analyses propose these mutations as the most likely cause of the disease, according to its frequency, in silico predictors, conservation analyses, and effect on the protein product. Additionally, we confirmed one mutation in each parent, supporting a compound heterozygous status in the child. CONCLUSIONS: In general, we think that this finding can contribute to the use of whole genome sequencing as a diagnosis tool of rare diseases, and in particular, it can enhance the set of known mutations associated with different diseases.
Asunto(s)
Arteriopatías Oclusivas/genética , Proteínas de Ciclo Celular/genética , Cardiopatías Congénitas/genética , Enfermedades Raras/genética , Factores de Transcripción/genética , Arteriopatías Oclusivas/diagnóstico , Arteriopatías Oclusivas/patología , Arterias/diagnóstico por imagen , Arterias/patología , Niño , Femenino , Mutación del Sistema de Lectura/genética , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/patología , Homocigoto , Humanos , Linaje , Enfermedades Raras/diagnóstico , Enfermedades Raras/patología , Secuenciación Completa del GenomaRESUMEN
Rare diseases comprise a diverse group of conditions, most of which involve genetic causes. We describe the variable spectrum of findings and clinical impacts of exome sequencing (ES) in a cohort of 500 patients with rare diseases. In total, 164 primary findings were reported in 158 patients, representing an overall diagnostic yield of 31.6%. Most of the findings (61.6%) corresponded to autosomal dominant conditions, followed by autosomal recessive (25.6%) and X-linked (12.8%) conditions. These patients harbored 195 variants, among which 43.6% are novel in the literature. The rate of molecular diagnosis was considerably higher for prenatal samples (67%; 4/6), younger children (44%; 24/55), consanguinity (50%; 3/6), gastrointestinal/liver disease (44%; 16/36) and syndromic/malformative conditions (41%; 72/175). For 15.6% of the cohort patients, we observed a direct potential for the redirection of care with targeted therapy, tumor screening, medication adjustment and monitoring for disease-specific complications. Secondary findings were reported in 37 patients (7.4%). Based on cost-effectiveness studies in the literature, we speculate that the reports of secondary findings may influence an increase of 123.2 years in the life expectancy for our cohort, or 0.246 years/cohort patient. ES is a powerful method to identify the molecular bases of monogenic disorders and redirect clinical care.
Asunto(s)
Exoma , Enfermedades Raras , Niño , Estudios de Cohortes , Consanguinidad , Exoma/genética , Femenino , Humanos , Embarazo , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Secuenciación del ExomaRESUMEN
This study discusses actors and institution movements leading to the disclosure in 2014 of Resolution 199 by the Brazilian Ministry of Health, which establishes the National Policy for the Comprehensive Care of Persons with Rare Diseases. Taking as sources the mainstream newspapers, drafts law, and secondary literature on the subject, we begin our analysis in the early 1990s when the first patient associations were created in Brazil - mainly for claiming more funds for research on genetic diseases - and arrive at the late 2010s when negotiations for a national policy are taking place in the National Congress. Resolution 199 is part of an ongoing process and the path towards its disclosure and the complications that followed have given us elements to discuss contemporary aspects of the Brazilian public health. Based on the references of the history of the present time and the social studies of science, we argue that two aspects have been fundamental to creating a national policy: framing different illnesses within the terminology "rare diseases" and the construction of a public perception about the right of health which is guaranteed by the 1988 Brazilian Constitution.
En este trabajo se analizan los movimientos de actores e instituciones que llevaron a la promulgación, en 2014, de la Resolución 199 del Ministerio de Salud de Brasil, que establece la Política Nacional de Atención Integral a las Personas con Enfermedades Raras. Tomando como fuentes los principales periódicos, proyectos de ley y bibliografía secundaria sobre el tema, comenzamos nuestro análisis a principios de la década de 1990 con la creación de las primeras asociaciones de pacientes en Brasil, para reclamar fundamentalmente más fondos para la investigación de enfermedades genéticas, y llegamos a fines de la década de 2010 con las negociaciones para una política nacional. La Resolución 199 es parte de un proceso en curso, en el que el camino hacia la promulgación y las complicaciones posteriores nos dan elementos para discutir aspectos actuales de la salud pública brasileña. Sobre la base de la historia del tiempo presente y los estudios sociales de la ciencia, argumentamos que hay dos aspectos que han sido fundamentales para crear una política nacional: enmarcar diferentes enfermedades en la terminología "enfermedades raras" y la construcción de una percepción pública sobre el derecho a la salud, que se garantiza en la Constitución brasileña de 1988.
Asunto(s)
Enfermedades Genéticas Congénitas , Genética Médica , Política de Salud , Programas Nacionales de Salud , Enfermedades Raras , Brasil , Prestación Integrada de Atención de Salud/historia , Prestación Integrada de Atención de Salud/legislación & jurisprudencia , Enfermedades Genéticas Congénitas/historia , Enfermedades Genéticas Congénitas/terapia , Genética Médica/historia , Política de Salud/economía , Política de Salud/historia , Política de Salud/legislación & jurisprudencia , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Programas Nacionales de Salud/economía , Programas Nacionales de Salud/historia , Programas Nacionales de Salud/legislación & jurisprudencia , Programas Nacionales de Salud/organización & administración , Periódicos como Asunto , Derechos del Paciente , Política , Enfermedades Raras/clasificación , Enfermedades Raras/genética , Enfermedades Raras/historia , Enfermedades Raras/terapia , Grupos de Autoayuda/historia , Grupos de Autoayuda/organización & administración , Terminología como AsuntoRESUMEN
Chromosomal abnormalities are responsible for several congenital malformations in the world, some of these are associated to telomeric/subtelomeric deletions. The abnormalities involving the telomere of chromosome 12 are rare, with few reports of deletions involving 12q24.31 region in the literature, and, to our knowledge, only four of them in the 12q24.31-q24.33 region. We report a further case of interstitial deletion of bands 12q24.31-q24.33 associated with autism spectrum disorder. A 2-year-old boy with global developmental delay associated with multiple congenital anomalies. The Human Genome CGH Microarray 60K confirmed the diagnosis of 12q deletion syndrome. This study made a review of the current literature comparing our patient with previously reported cases. These detailed analyses contribute to the development of genotype/phenotype correlations for 12q deletions that will aid in better diagnosis and prognosis of this deletion.
Asunto(s)
Trastorno del Espectro Autista/genética , Trastorno Autístico/genética , Trastornos de los Cromosomas/patología , Cromosomas Humanos Par 12/genética , Enfermedades Raras/genética , Anomalías Múltiples , Preescolar , Aberraciones Cromosómicas , Deleción Cromosómica , Humanos , MasculinoAsunto(s)
Anemia/genética , Eliptocitosis Hereditaria/genética , Glucosafosfato Deshidrogenasa/genética , Mutación , Piruvato Quinasa/genética , Anemia/diagnóstico , República Dominicana , Salud de la Familia , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Humanos , Recién Nacido , Patrón de Herencia/genética , Masculino , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Gemelos Monocigóticos/genéticaRESUMEN
ABSTRACT Chromosomal abnormalities are responsible for several congenital malformations in the world, some of these are associated to telomeric/subtelomeric deletions. The abnormalities involving the telomere of chromosome 12 are rare, with few reports of deletions involving 12q24.31 region in the literature, and, to our knowledge, only four of them in the 12q24.31-q24.33 region. We report a further case of interstitial deletion of bands 12q24.31-q24.33 associated with autism spectrum disorder. A 2-year-old boy with global developmental delay associated with multiple congenital anomalies. The Human Genome CGH Microarray 60K confirmed the diagnosis of 12q deletion syndrome. This study made a review of the current literature comparing our patient with previously reported cases. These detailed analyses contribute to the development of genotype/phenotype correlations for 12q deletions that will aid in better diagnosis and prognosis of this deletion.
RESUMO Anomalias cromossômicas são responsáveis por inúmeras malformações congênitas no mundo, algumas delas associadas a deleções teloméricas/subteloméricas. As anomalias que envolvem o telômero do cromossomo 12 são raras, com poucos relatos na literatura sobre deleções relacionados à região 12q24.31 e, até onde sabemos, apenas quatro deles na região 12q24.31-q24.33. Relatamos um outro caso de deleção intersticial das bandas 12q24.31-q24.33 associada ao transtorno do espectro do autismo. Trata-se de um menino de 2 anos de idade com atraso global no desenvolvimento associado a múltiplas anomalias congênitas. A utilização do Human Genome CGH Microarray 60K confirmou o diagnóstico da síndrome de deleção 12q. Este estudo fez uma revisão da literatura atual, comparando nosso paciente com casos previamente relatados. Estas análises detalhadas contribuem para o desenvolvimento de correlações genótipo/fenótipo para deleções 12q, que ajudam aos melhores diagnóstico e prognóstico desta deleção.
Asunto(s)
Humanos , Masculino , Preescolar , Trastorno Autístico/genética , Cromosomas Humanos Par 12/genética , Trastornos de los Cromosomas/patología , Enfermedades Raras/genética , Trastorno del Espectro Autista/genética , Anomalías Múltiples , Aberraciones Cromosómicas , Deleción CromosómicaRESUMEN
BACKGROUND: Approximately 50% of cases of penile carcinoma (PeCa), a rare neoplasm worldwide, are associated with human papillomavirus (HPV). However, the detection of HPV-DNA is not sufficient to consider it the etiological factor in the development of this type of cancer. Currently, the overexpression of P16INK4A is used as a surrogate biomarker of HPV carcinogenesis. Information on PeCa in Mexico is scarce, particularly regarding cases related to HPV and genotype frequency. OBJECTIVE: To evaluate the presence of HPV, its genotypes, and the presence of multiple genotypes, and the expression of P16INK4A, as well as its clinical and histopathological parameters. METHODS: For HPV-DNA detection and P16INK4A expression, we used the INNO-LiPA® test and immunohistochemistry, respectively. RESULTS: Sixty cases of PeCa were evaluated, of which 75% were HPV-non-related histological variants. We found that 58.9% (33/56) of PeCa cases were HPV-DNA positive, while 30.9% of the cases evaluated (17/55) were positive for P16INK4A. HPV16 was the main genotype in 42.9% of the cases, followed by HPV52 in 7.1% and HPV18 in 5.4%. Within the HPV-positive cases, 27.3% had multiple genotypes. All HPV-positive patients under the age of 45 years were positive only for HPV16. CONCLUSIONS: HPV16 was the most commonly detected genotype in PeCa. HPV 31, 35 and 39 were infrequent; however, they were related to a single infection and P16INK4A overexpression; thus, they seem to be relevant in PeCa carcinogenesis. Our results suggest that P16INK4A overexpression could be useful for the classification of HPV-related PeCa. The role of multiple HPV genotypes in the development and prognosis of PeCa is still not completely understood. Thus, it is necessary to define criteria to establish reliable ways to classify HPV-related PeCa that could lead to optimal therapeutic approaches.
Asunto(s)
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/virología , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Papillomavirus Humano 16/genética , Infecciones por Papillomavirus/genética , Infecciones por Papillomavirus/virología , Neoplasias del Pene/genética , Neoplasias del Pene/virología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Carcinoma de Células Escamosas/clasificación , Genotipo , Humanos , Inmunohistoquímica , Masculino , México , Persona de Mediana Edad , Infecciones por Papillomavirus/clasificación , Neoplasias del Pene/clasificación , Pronóstico , Enfermedades Raras/genética , Enfermedades Raras/virología , Adulto JovenRESUMEN
The first draft of the human genome sequencing published in 2001 reported a large number of single nucleotide polymorphisms (SNPs). Given that these polymorphisms could practically represent all the variability involved in the susceptibility, protection, severity, among other aspects, of various common diseases, as well as in their response to medications, it was thought that they might be "the biomarkers of choice" in personalized genomic medicine. With the new information obtained from the sequencing of a larger number of genomes, we have understood that SNPs are only an important part of the genetic markers involved in these traits. In addition to SNPs, other variants have been identified, such as insertions/deletions (INDELs) and copy number variants (CNVs), which - in addition to classic variable number tandem repeats (VNTRs) and short tandem repeats (STRs) - originate or contribute to the development of diseases. The use of these markers has served to identify regions of the genome involved in Mendelian diseases (one gene-one disease) or genes directly associated with multifactorial diseases. This review has the purpose to describe the role of STRs, VNTRs, SNPs, CNVs and INDELs in linkage and association studies and their role in Mendelian and multifactorial diseases.
El primer borrador de la secuencia del genoma humano, publicado en 2001, reportó gran cantidad de variantes de un solo nucleótido (SNP, single nucleotide polymorphisms). Debido a que estos polimorfismos podrían representar prácticamente toda la variabilidad involucrada en la susceptibilidad, protección, gravedad, etcétera, de diversas enfermedades comunes, así como en la respuesta de estas a los medicamentos, se pensó que podrían ser "los biomarcadores de elección" en la medicina genómica personalizada. Con la nueva información de la secuenciación de un mayor número de genomas hemos comprendido que los SNP son solo una parte importante de los marcadores genéticos involucrados en estos rasgos. Además de los SNP, se han identificado que otras variantes como las inserciones/deleciones (INDEL) y las variantes en el número de copia (CNV), las cuales además de los clásicos repetidos en tándem de número variable (VNTR) y repetidos cortos en tándem (STR) originan o contribuyen al desarrollo de enfermedades. El uso de estos marcadores ha servido para identificar regiones del genoma involucradas en enfermedades mendelianas (un gen-una enfermedad) o genes directamente asociados con enfermedades multifactoriales. Esta revisión tiene como objetivo describir el papel de los STR, VNTR, SNP, CNV e INDEL en los estudios de ligamiento y asociación, y su papel en las enfermedades mendelianas y multifactoriales.