RESUMEN
Hereditary breast and ovarian cancer (HBOC) syndrome is a genetic condition that increases the risk of breast cancer by 80% and that of ovarian cancer by 40%. The most common pathogenic variants (PVs) causing HBOC occur in the BRCA1 gene, with more than 3850 reported mutations in the gene sequence. The prevalence of specific PVs in BRCA1 has increased across populations due to the effect of founder mutations. Therefore, when a founder mutation is identified, it becomes key to improving cancer risk characterization and effective screening protocols. The only founder mutation described in the Mexican population is the deletion of exons 9 to 12 of BRCA1 (BRCA1Δ9-12), and its description focuses on the gene sequence, but no transcription profiles have been generated for individuals who carry this gene. In this study, we describe the transcription profiles of cancer patients and healthy individuals who were heterozygous for PV BRCA1Δ9-12 by analyzing the differential expression of both alleles compared with the homozygous BRCA1 control group using RT-qPCR, and we describe the isoforms produced by the BRCA1 wild-type and BRCA1Δ9-12 alleles using nanopore long-sequencing. Using the Kruskal-Wallis test, our results showed a similar transcript expression of the wild-type allele between the healthy heterozygous group and the homozygous BRCA1 control group. An association between the recurrence and increased expression of both alleles in HBOC patients was also observed. An analysis of the sequences indicated four wild-type isoforms with diagnostic potential for discerning individuals who carry the PV BRCA1Δ9-12 and identifying which of them has developed cancer.
Asunto(s)
Alelos , Proteína BRCA1 , Síndrome de Cáncer de Mama y Ovario Hereditario , Humanos , Proteína BRCA1/genética , Femenino , Síndrome de Cáncer de Mama y Ovario Hereditario/genética , Persona de Mediana Edad , Predisposición Genética a la Enfermedad , Adulto , Efecto Fundador , Exones/genética , Neoplasias de la Mama/genética , Heterocigoto , Mutación , México , Neoplasias Ováricas/genética , Relevancia ClínicaRESUMEN
Lynch syndrome (LS) is the main hereditary colorectal cancer syndrome. There have been few reports regarding the clinical and molecular characteristics of LS patients in Latin America; this is particularly true in the Mexican population, where no information is available. The present study aims to describe the clinical and molecular spectrum of variants in a cohort of patients diagnosed with LS in Mexico. We present a retrospective analysis of 412 patients with suspected LS, whose main site of cancer diagnosis was the colon (58.25%), followed by the endometrium (18.93%). Next-generation sequencing analysis, with an extensive multigene panel, showed that 27.1% (112/414) had a variant in one of the genes of the mismatch repair pathway (MMR); 30.4% (126/414) had a variant in non-MMR genes such as CHEK2, APC, MUTYH, BRCA1, and BRCA2; and 42.5% (176/414) had no genetic variants. Most of the variants were found in MLH1. Pathogenic variants (PVs) in MMR genes were identified in 65.7% (96/146) of the total PVs, and 34.24% (45/146) were in non-MMR genes. Molecular and clinical characterization of patients with LS in specific populations allowed personalized follow-up, with the option for targeted treatment with immune checkpoint inhibitors and the development of public health policies. Moreover, such characterization allows for family cascade testing and consequent prevention strategies.
Asunto(s)
Neoplasias Colorrectales Hereditarias sin Poliposis , Neoplasias Colorrectales Hereditarias sin Poliposis/diagnóstico , Neoplasias Colorrectales Hereditarias sin Poliposis/epidemiología , Neoplasias Colorrectales Hereditarias sin Poliposis/genética , Reparación de la Incompatibilidad de ADN/genética , Proteínas de Unión al ADN/genética , Femenino , Mutación de Línea Germinal , Humanos , Inhibidores de Puntos de Control Inmunológico , México/epidemiología , Proteína 2 Homóloga a MutS/genética , Estudios RetrospectivosRESUMEN
The deletion of exons 9 to 12 of BRCA1 (9-12 del BRCA1) is considered a founder mutation in the Mexican population. We evaluate the usefulness of the target detection of 9-12 del BRCA1 as the first molecular diagnostic strategy in patients with Hereditary Breast and Ovarian Cancer (HBOC). We performed the genetic assessment of 637 patients with suspected HBOC. The region corresponding to the breakpoints for the 9-12 del BRCA1 was amplified by polymerase chain reaction (PCR). An analysis of the clinical data of the carriers and non-carriers was done, searching for characteristics that correlated with the deletion. The 9-12 del BRCA1 was detected in 5% of patients with suspected HBOC (30/637). In patients diagnosed with ovarian cancer, 13 of 30 were 9-12 del BRCA1 carriers, which represents 43%. We found a significant association between the 9-12 del BRCA1 carriers with triple negative breast cancer and high-grade papillary serous ovarian cancer. We concluded that the detection of the 9-12 del BRCA1 is useful as a first molecular diagnostic strategy in the Mexican population. In particular, it shortens the gap in genetic assessment in patients with triple negative breast cancer and ovarian cancer.
Asunto(s)
Proteína BRCA1/genética , Neoplasias de la Mama/genética , Predisposición Genética a la Enfermedad/genética , Mutación de Línea Germinal , Neoplasias Ováricas/genética , Adulto , Neoplasias de la Mama/diagnóstico , Exones/genética , Salud de la Familia , Femenino , Efecto Fundador , Pruebas Genéticas , Humanos , México , Persona de Mediana Edad , Neoplasias Ováricas/diagnóstico , Eliminación de Secuencia , Adulto JovenRESUMEN
Congenital macroglossia is a condition that consists in an enlarged tongue that in resting position protrudes beyond the alveolar ridge. It has been classified in two categories: true macroglossia, which occurs in congenital or acquired forms, and relative macroglossia. As this alteration may be due to different causes, its incidence is not known. It is more frequently associated to Beckwith-Wiedemann syndrome, to mucopolysaccharidosis diseases and to Pompe's disease, and it has been less frequently associated to lymphangioma, hemangioma or isolated muscular hypertrophy. Macroglossia is characterized by an enlarged and thick tongue that may have fissures and ulcers, may cause language alterations, difficulties for feeding and swallowing, sialorrhea and recurrent infections of the upper airway or even its obstruction. Its clinical evaluation must include a complete clinical chart with careful physical exploration and a pedigree of that may identify the presence or absence of a hereditary associated syndrome. Macroglossia management is complex. More than twenty different surgical options to reduce the tongue size have been proposed, however, so far there is not a general agreement in this respect. The objective of this work is to review clinical and surgical aspects related to macroglossia from the point of view of non-surgical pediatricians and genetists, addressed to the different medical specialists, including the maxillofacial surgeons involved in the management of these patients.
RESUMEN
INTRODUCTION: Velocardiofacial syndrome (VCFS) is the most common microdeletion syndrome with an incidence of 1:4000 live births. Its phenotype is highly variable with facial, velopharyngeal, cardiac, endocrine, immunologic and psychiatric abnormalities. It is caused by a microdeletion in chromosome 22q11.2. OBJECTIVES: We present 7 years of experience evaluating patients with VCFS regarding their main clinical characteristics. MATERIAL AND METHODS: The patients included were multidisciplinary evaluated and had a positive FISH analysis for del22q11.2. RESULTS: A total of 62 patients were assessed, a 34 female/28 male ratio was observed with ages ranging from 9 days to 16 years, all but one patient had typical facial features. A diagnosis of congenital heart disease was established in 97% of the patients; other clinical characteristics were identified with different percentages such as cleft palate, and hypocalcaemia. Three cases had a familial presentation. DISCUSSION: While the clinical findings of this study were in general terms in keeping with the literature, it is interesting the unexpectedly high percentage of congenital heart disease identified in Mexican children with VCFS that also was the main cause for clinical referral.
Asunto(s)
Síndrome de DiGeorge/etnología , Cardiopatías Congénitas/complicaciones , Adolescente , Niño , Preescolar , Cromosomas Humanos Par 22/genética , Síndrome de DiGeorge/complicaciones , Síndrome de DiGeorge/genética , Femenino , Cardiopatías Congénitas/diagnóstico , Cardiopatías Congénitas/etnología , Humanos , Hibridación Fluorescente in Situ , Lactante , Recién Nacido , Masculino , México , Fenotipo , PrevalenciaRESUMEN
Resumen: La macroglosia congénita es una condición que se caracteriza por una lengua que en posición de reposo protruye más allá del borde alveolar; se ha clasificado en dos categorías: verdadera, que puede ser congénita o adquirida, y relativa. Debido a la asociación de esta alteración con múltiples causas, su incidencia es variable. Es más frecuente que la macroglosia se asocie con el síndrome de Beckwith-Wiedemann, con las mucopolisacaridosis y con la enfermedad de Pompe, y con menor frecuencia a linfangioma, hemangioma o hipertrofia muscular aislada. La macroglosia se caracteriza por una lengua alargada, engrosada o ancha, protruida crónicamente en reposo, con presencia o no de fisuras y úlceras, alteraciones del lenguaje, dificultad para la alimentación y deglución, sialorrea e infecciones recurrentes de la vía respiratoria superior u obstrucción de la misma. Su valoración en niños debe iniciarse con una historia clínica y exploración física completas y con la elaboración de un árbol genealógico de al menos tres generaciones, además de investigar la presencia o no de una entidad sindrómica. Se han propuesto más de 20 técnicas quirúrgicas para resolver la macroglosia congénita; sin embargo, a la fecha no existe consenso para la aplicación de una técnica en particular para reducir su tamaño. En esta revisión se pretende destacar los aspectos clínicos y quirúrgicos de la macroglosia, desde la perspectiva de pediatras no cirujanos y genetistas, dirigido a la comunidad de especialistas médicos que atiende a estos pacientes incluyendo a los cirujanos maxilofaciales que atienden a estos pacientes.
Abstract: Congenital macroglossia is a condition that consists in an enlarged tongue that in resting position protrudes beyond the alveolar ridge. It has been classified in two categories: true macroglossia, which occurs in congenital or acquired forms, and relative macroglossia. As this alteration may be due to different causes, its incidence is not known. It is more frequently associated to Beckwith-Wiedemann syndrome, to mucopolysaccharidosis diseases and to Pompe's disease, and it has been less frequently associated to lymphangioma, hemangioma or isolated muscular hypertrophy. Macroglossia is characterized by an enlarged and thick tongue that may have fissures and ulcers, may cause language alterations, difficulties for feeding and swallowing, sialorrhea and recurrent infections of the upper airway or even its obstruction. Its clinical evaluation must include a complete clinical chart with careful physical exploration and a pedigree of that may identify the presence or absence of a hereditary associated syndrome. Macroglossia management is complex. More than twenty different surgical options to reduce the tongue size have been proposed, however, so far there is not a general agreement in this respect. The objective of this work is to review clinical and surgical aspects related to macroglossia from the point of view of non-surgical pediatricians and genetists, addressed to the different medical specialists, including the maxillofacial surgeons involved in the management of these patients.