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Couple screening aims to identify couples with an increased risk of having a child affected with an autosomal recessive or X-linked disorder, in order to facilitate informed reproductive decision making. Both expectant parents should be screened as a single entity, instead of individual testing. Carrier testing was typically performed for a few relatively common recessive disorders associated with significant morbidity, reduced life expectancy and often because of a considerably higher carrier frequency in a specific population for certain diseases. However, new genetic testing technologies enable the expansion of screening to multiple conditions, genes and sequence variants. There are multiple reproductive options for screening couples at risk, particularly when genetic traits are detected in the preconception period.

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PURPOSE: Cohort building is a powerful foundation for improving clinical care, performing biomedical research, recruiting for clinical trials, and many other applications. We set out to build a cohort of all monogenic patients with a definitive causal gene diagnosis in a 3-million patient hospital system. METHODS: We define a subset (4461) of OMIM diseases that have at least 1 known monogenic causal gene. We then introduce MonoMiner, a natural language processing framework to identify molecularly confirmed monogenic patients from free-text clinical notes. RESULTS: We show that ICD-10-CM codes cover only a fraction of monogenic diseases and that even where available, ICD-10-CM code‒based patient retrieval offers 0.14 precision. Searching by causal gene symbol offers great recall but has an even worse 0.07 precision. MonoMiner achieves 6 to 11 times higher precision (0.80), with 0.87 precision on disease diagnosis alone, tagging 4259 patients with 560 monogenic diseases and 534 causal genes, at 0.48 recall. CONCLUSION: MonoMiner enables the discovery of a large, high-precision cohort of patients with monogenic diseases with an established molecular diagnosis, empowering numerous downstream uses. Because it relies solely on clinical notes, MonoMiner is highly portable, and its approach is adaptable to other domains and languages.

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Resumen El síndrome nefrótico se define como la unión de proteinuria masiva, hipoalbuminemia e hiperlipidemia, que pueden asociarse a edemas e hipercoagulabilidad. Se origina de una anormalidad de la barrera de filtración glomerular con una fuga masiva de proteína y los efectos secundarios consecuentes. En sus formas primarias, ocurre con una incidencia de 1-3 por cada 100.000 niños menores de 16 años. La forma congénita es una variante poco frecuente del síndrome nefrótico, la cual se presenta en el nacimiento o dentro de los tres primeros meses de vida, y suele ser resistente a la corticoterapia. Se debe evaluar primero la existencia de infecciones congénitas y luego buscar las enfermedades monogénicas más comunes, finalmente se puede recurrir a la secuenciación de nueva generación para buscar mutaciones en los demás genes candidatos. Se presenta el caso de una niña con síndrome nefrótico congénito de difícil control, enfatizando en el proceso diagnóstico y el manejo de soporte. Se resalta la importancia de la asesoría genética a la familia en todos los casos.

Abstract A nephrotic syndrome is defined as the association of massive proteinuria, hypoalbuminemia and hyperlipidemia, which may be associated with edema and hypercoagulability. It originates from an abnormality of the glomerular filtration barrier with a massive protein leak and the consequent side effects. In its primary forms, it occurs with an incidence of 1 - 3 per 100,000 children under 16 years of age. The congenital form is a rare variant of the nephrotic syndrome, which occurs at birth or within the first three months of life and is usually resistant to corticosteroid therapy. Congenital infections and most common related monogenic diseases should be tested. Finally, new generation sequencing must be used to search for mutations in other candidate genes. We present the case of a girl with congenital nephrotic syndrome difficult to control, emphasizing the diagnostic process and support management. The importance of genetic counseling to the family in all cases is highlighted.

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OBJECTIVE: To describe the cases of preimplantation genetic testing for monogenic diseases (PGT-M) in fertile couples who had undergone intracytoplasmic sperm injection (ICSI) cycles in a Brazilian in vitro fertilisation (IVF) centre and determine whether these cases were different from those reported from the European Society of Human Reproduction and Embryology (ESHRE). METHODS: This retrospective collection included data obtained from ICSI-PGT-M cycles between 2011 and 2016. The disease indication, number of biopsied embryos, biopsy stage, diagnosed and affected embryos, and cycles with embryo to transfer as well as implantation, pregnancy and miscarriage rates were analysed and compared to cycles without genetic diagnosis (PGT) and with ESHRE PGD Consortium collection XIV-XV. RESULTS: From 5,070 cycles performed, 72 had indications for PGT-M. The most common time for biopsy was cleavage-stage; 93% of the embryos had a diagnostic result, 59.4% of which were genetically transferable, resulting in 68% of the cycles with transferred embryos, a 22.1% implantation rate, and a 28.6% pregnancy rate. No differences in clinical outcomes of cycles with PGT-M or without PGT were observed. The day of biopsy and diagnostic success as well as implantation, pregnancy and miscarriage rates were similar to ESHRE collection. CONCLUSIONS: Although the proportion of cases with PGT-M was low, its efficacy was similar to what was reported in the European collection and represents a viable alternative for families at risk of transmitting a genetic disorder to their offspring. The main difference between our and ESHRE collection were the disease indications, which reflected the admixed, multi-ethnic Brazilian population.

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Durante las últimas dos décadas, los resultados de varios protocolos de terapia génica llevaron al descreimiento de la comunidad médica. Sin embargo, en años recientes se obtuvieron resultados muy exitosos que la reposicionaron como una opción prometedora para el tratamiento de muchas enfermedades. Frente a este resurgimiento del interés de la comunidad científca internacional en la terapia génica, resulta apropiado que el médico generalista comprenda sus fortalezas y limitaciones. El objetivo de este artículo es comentar la forma en que la terapia génica encara actualmente el tratamiento de patologías tan diversas como neoplasias, infecciones y enfermedades monogénicas.

During the last two decades, the outcome of various gene therapy protocols lead to medical community disbelief. Nevertheless, successful results obtained in recent years, repositioned gene therapy as a promising option for treatment of several diseases. Facing this renaissance of the international scientifc community interest on gene therapy, it seems to be necessary for the generalist physician to understand its strength and limitations. The objective of this article is to comment the way gene therapy addresses nowadays the treatment of such different pathologies as neoplasias, infections and monogenic diseases.

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