De novo variants in GABRA4 are associated with a neurological phenotype including developmental delay, behavioral abnormalities and epilepsy.

Nine out of 19 genes encoding GABAA receptor subunits have been linked to monogenic syndromes characterized by seizures and developmental disorders. Previously, we reported the de novo variant p.(Thr300Ile) in GABRA4 in a patient with epilepsy and neurodevelopmental abnormalities. However, no new cases have been reported since then. Through an international collaboration, we collected molecular and phenotype data of individuals carrying de novo variants in GABRA4. Patients and their parents were investigated either by exome or genome sequencing, followed by targeted Sanger sequencing in some cases. All variants within the transmembrane domain, including the previously reported p.(Thr300Ile) variant, were characterized in silico and analyzed by molecular dynamics (MD) simulation studies. We identified three novel de novo missense variants in GABRA4 (NM_000809.4): c.797 C > T, p.(Pro266Leu), c.899 C > A, p.(Thr300Asn), and c.634 G > A, p.(Val212Ile). The p.(Thr300Asn) variant impacts the same codon as the previously reported variant p.(Thr300Ile) and likely arose post-zygotically as evidenced by sequencing oral mucosal cells. Overlapping phenotypes among affected individuals included developmental delay (4/4), epileptiform EEG abnormalities (3/4), attention deficits (3/4), seizures (2/4), autistic features (2/4) and structural brain abnormalities (2/4). MD simulations of the three variants within the transmembrane domain of the receptor indicate that sub-microsecond scale dynamics differ between wild-type and mutated subunits. Taken together, our findings further corroborate an association between GABRA4 and a neurological phenotype including variable neurodevelopmental, behavioral and epileptic abnormalities.

Real-world economic evaluation of prospective rapid whole-genome sequencing compared to a matched retrospective cohort of critically ill pediatric patients in the United States.

There is an increasing demand for supporting the adoption of rapid whole-genome sequencing (rWGS) by demonstrating its real-world value. We aimed to assess the cost-effectiveness of rWGS in critically ill pediatric patients with diseases of unknown cause. Data were collected prospectively of patients admitted to the Nicklaus Children's Hospital's intensive care units from March 2018 to September 2020, with rWGS (N = 65). Comparative data were collected in a matched retrospective cohort with standard diagnostic genetic testing. We determined total costs, diagnostic yield (DY), and incremental cost-effectiveness ratio (ICER) adjusted for selection bias and right censoring. Sensitivity analyses explored the robustness of ICER through bootstrapping. rWGS resulted in a diagnosis in 39.8% while standard testing in 13.5% (p = 0.026). rWGS resulted in a mean saving per person of $100,440 (SE = 26,497, p < 0.001) and a total of $6.53 M for 65 patients. rWGS in critically ill pediatric patients is cost-effective, cost-saving, shortens diagnostic odyssey, and triples the DY of traditional approaches.

Sustancias sicoactivas: escala de riesgo / Psychoactive substances: risk scale

El proceso historico ha mostrado como el uso de los sicoactivos cambia con las sociedades y con el tiempo y su valoracion depende en gran medida del tipo de organizacion. En la actualidad el impresionante desarrollo tecnologico en la comunicacion, tanto en el sofisticamiento de sus tecnicas, como en la diversidad de las mismas hace que el individuo este permanentemente sometido a una multidtud de mensajes de variada indole y contenido, entre otros sobre la droga. En Colombia segun lo encontrado por la Encuesta CAPS el 90 por ciento de las personas son radioescuchas y el 80 por ciento son televidentes asiduos. Aqui aparece el primer interrogante, estan estos medios de comunicacion siendo estimulos para que la poblacion se interse por la droga no siempre de una manera adecuada? Debido a la metodologia empleada por la Encuesta CAPS el enfasis del analisis de los resultados esta en determinar los conocimientos, las actitudes y el riesgo a consumir los sicoactivos de estudio y no en el consumo de los mismos, para el cual se hacen estimaciones globales solamente. La poblacion colombiana de 15 a 59 anos entrevistada por CAPS se mostro conservadora con respecto a permitir el libre consumo y el libre comercio de la marihuana, el basuco y la cocaina. Cerca del 96 por ciento de los encuestados no esta de acuerdo con que este evento deba darse. Sin embargo el perfil de los que opinan que debe permitirse es interesante; existe mayor proporcion de respuestas positivas para la permisibilidad de la marihuna que para el basuco y la cocaina, tanto en su consumo como en su comercio. Ademas se observa una tendencia de las personas a estar mas inclinadas..