Purpose: Hereditary Breast and Ovarian Cancer (HBOC) syndrome is responsible for ∼5-10% of all diagnosed breast and ovarian cancers. Breast cancer is the most common malignancy and the leading cause of cancer-related mortality among women in Latin America (LA). The main objective of this study was to develop a comprehensive understanding of the genomic epidemiology of HBOC throughout the establishment Oliver et al. Latin American HBOC Study of The Latin American consortium for HBOC-LACAM, consisting of specialists from 5 countries in LA and the description of the genomic results from the first phase of the study. Methods: We have recruited 403 individuals that fulfilled the criteria for HBOC from 11 health institutions of Argentina, Colombia, Guatemala, Mexico and Peru. A pilot cohort of 222 individuals was analyzed by NGS gene panels. One hundred forty-three genes were selected on the basis of their putative role in susceptibility to different hereditary cancers. Libraries were sequenced in MiSeq (Illumina, Inc.) and PGM (Ion Torrent-Thermo Fisher Scientific) platforms. Results: The overall prevalence of pathogenic variants was 17% (38/222); the distribution spanned 14 genes and varied by country. The highest relative prevalence of pathogenic variants was found in patients from Argentina (25%, 14/57), followed by Mexico (18%, 12/68), Guatemala (16%, 3/19), and Colombia (13%, 10/78). Pathogenic variants were found in BRCA1 (20%) and BRCA2 (29%) genes. Pathogenic variants were found in other 12 genes, including high and moderate risk genes such as MSH2, MSH6, MUTYH, and PALB2. Additional pathogenic variants were found in HBOC unrelated genes such as DCLRE1C, WRN, PDE11A, and PDGFB. Conclusion: In this first phase of the project, we recruited 403 individuals and evaluated the germline genetic alterations in an initial cohort of 222 patients among 4 countries. Our data show for the first time in LA the distribution of pathogenic variants in a broad set of cancer susceptibility genes in HBOC. Even though we used extended gene panels, there was still a high proportion of patients without any detectable pathogenic variant, which emphasizes the larger, unexplored genetic nature of the disease in these populations.

Disorders of sex development (DSDs) are congenital conditions in which the external appearance of the individual does not coincide with the chromosomal constitution or the gonadal sex. In other words, there is an ambiguous or intermediate condition between the male and female phenotypes of the anatomical sex. These atypical conditions are manifested in several ways, ranging from genital ambiguity to phenotypes that are so attenuated that they can go unnoticed or appear normal. Currently, there is a lack of understanding of the factors responsible for these outcomes; however, they are likely to be conditioned by genetic, hormonal and environmental factors during prenatal and postnatal development. The present study determined the genetic etiology of DSDs in Colombian patients by conventional cytogenetic analysis, FISH and MLPA (for SF1, DAX1, SOX9, SRY and WNT4). A cohort of 43 patients with clinical phenotypes of sex development disorder was used in the present study. Using this multistep experimental approach, a diagnostic percentage of 25.58% was obtained: 17 patients (39.53%) were classified as having gonadal development disorders, the majority of which were ovotesticular disorders with numerical and/or structural alterations of the sex chromosomes, 9 patients (20.93%) were classified as having testicular DSD with a 46,XY karyotype, and 3 patients (6.98%) as having ovarian DSD with a 46,XX karyotype. The remaining 14 patients (32.56%) were classified as ‘other’ since they could not be grouped into a specific class of gonadal development, corresponding to hypospadias and multiple congenital anomalies. These findings highlight the importance of histological and cytogenetic studies in a gonadal biopsy. In 11/43 cases, the multistep experimental protocol presented in the present study yielded etiological or histological findings that could be used to define the medical management of patients with DSDs. In conclusion, for the etiological diagnosis of DSDs, a broad-spectrum approach that includes endocrinological tests, conventional karyotyping, molecular karyotyping by FISH and, molecular tests is required, in addition to gonadal tissue analyses, to identify genetic alterations.

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Introducción. Las mucopolisacaridosis son enfermedades poco frecuentes de depósito lisosómico de glucosaminoglucanos, con datos variables sobre su incidencia en diferentes países a nivel mundial. En Latinoamérica hay reportes de frecuencias en Brasil, pero en Colombia la información es escasa. Objetivos. Estimar las frecuencias de las mucopolisacaridosis mediante un estudio retrospectivo en los departamentos de Cundinamarca y Boyacá, y estimar la agregación espacial de los casos en estos mismos departamentos. Materiales y métodos. Se revisaron los registros de pacientes de diferentes instituciones de referencia para enfermedades genéticas, así como los registros de nacimientos vivos entre 1998 y 2007. Con base en ellos, se estimaron las frecuencias para cada tipo de mucopolisacaridosis. Se analizó la agregación espacial de los casos utilizando el programa SaTScan™. Resultados. La frecuencia combinada para todas las mucopolisacaridosis fue de 1,98 casos por 100.000 nacidos vivos. La mayor frecuencia fue para la de tipo IV, con 0,68 casos por 100.000 nacidos vivos, mientras que la III fue la menor, con 0,17 casos. Se encontraron tres posibles áreas de agregación espacial para las mucopolisacaridosis I, III y IV. Conclusión. La frecuencia combinada para todas las mucopolisacaridosis se encuentra dentro de los rangos reportados en la literatura científica, siendo la de tipo IV la más frecuente y la de tipo VII la menos frecuente. Aunque los datos aquí reportados podrían corresponder a un subregistro, dadas las dificultades inherentes a la recolección de la información en nuestro país, consideramos que son un estimativo válido de las frecuencias de estas enfermedades.Palabras clave: mucopolisacaridosis/epidemiología, errores innatos del metabolismo, enfermedades por almacenamiento lisosómico, análisis por conglomerados. doi: http://dx.doi.org/10.7705/biomedica.v32i4.574 Estimation of the mucopolysaccharidoses frequencies and cluster analysis in the Colombian provinces of Cundinamarca and BoyacáIntroduction. Mucopolysaccharidoses are a group of infrequent disorders caused by the lysosomal deposit of glycosaminoglycans. Its incidence is quite variable among thecountries where it has been documented. In Brazil, disorder frequencies have been reported, but in Colombia information on them is scarce. Objectives. The frequency and spatial aggregations of the mucopolysaccharidoses were estimated by a retrospective study in two central Colombian provinces. Materials and methods. The records of patients and live newborns between 1998-2007 were reviewed from several reference institutions for genetic diseases. From these records, the frequencies for each mucopolysaccharidosis were estimated. The spatial aggregation of the cases was analyzed using the SaTScan software. Results. The combined frequency for all the mucopolysaccharidoses was 1.98 cases per 100,000 live newborns. MPS IV had the highest frequency with 0.68 cases per 100,000 live newborns and MPS III showed a lower frequency of 0.17/100,000. Three spatial aggregation a...

Background Fabry disease is an X‐linked lysosomal storage disorder with heterogeneous clinical expression in female patients ranging from asymptomatic to severe clinical presentations as in classic males. We assessed clinical profiles and compared natural history data of female patients eventually initiated on enzyme replacement therapy (“ERT‐recipients”) with those remaining untreated (“ERT‐naïve”). Methods We analyzed Fabry Registry data from 93 ERT‐recipients, collected prior to ERT initiation, and 76 ERT‐naïve females with classic or unclassified phenotypes from four Latin American countries and evaluated Fabry symptoms, interventricular septum thickness, left ventricular posterior wall thickness, estimated glomerular filtration rate, and severe clinical events. Results For 169 patients with available data, median age of first Fabry symptom manifestation was 12.7 years with peripheral pain as predominant first symptom, and diagnostic delay of 10.3 years from the first reported symptom. Female patients had high symptomatic burden during natural history follow‐up, with 83% reporting peripheral pain, 69%‐79% cold/heat intolerance or abnormal sweating, and 32% gastrointestinal symptoms. ERT‐recipients reported similar age at first symptom as ERT‐naïve patients but they were older at diagnosis (median 39.2 vs 24.4 years, P < .01) and last follow‐up (median 43.4 vs 28.2 years, P < .01). Reported Fabry symptom frequencies and abnormal echocardiography findings were higher in ERT‐recipients. Functional renal assessments were normal and similar. Conclusions Female patients from Latin America have notable diagnostic delays and high symptomatic burden. ERT was prescribed late in females with advanced age at diagnosis and advanced disease. There remained many female patients who had been diagnosed at younger age, had substantial Fabry manifestations, but did not receive disease‐specific treatment.

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Fanconi anemia is a genetic syndrome clinically characterized by congenital malformations that affect several human systems, leads to progressive bone marrow failure and predisposes an individual to cancer, particularly in the urogenital area as well as the head and neck. It is commonly caused by the biallelic compromise of one of 22 genes involved in the FA/BRCA repair pathway in most cases. The diagnosis is based on clinical suspicion and confirmation using genetic analysis, where the chromosomal breakage test is considered the gold standard. Other diagnostic methods used include western blotting, multiplex ligation-dependent probe amplification and next-generation sequencing. This genetic condition has variable expressiveness, which makes early diagnosis difficult in certain cases. Although early diagnosis does not currently allow for improved cure rates for this condition, it does enable healthcare professionals to perform a specific systematic follow-up and, if indicated, a bone marrow transplantation that improves the mobility and mortality of affected individuals. The present review article is a theoretical revision of the pathophysiology, clinical manifestations and diagnosis methods intended for different specialists and general practitioners to improve the diagnosis of this condition.

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