Genetic profiling of children with advanced cholestatic liver disease.

Advanced cholestatic liver disease is a leading referral to pediatric liver transplant centers. Recent advances in the genetic classification of this group of disorders promise a highly personalized management although the genetic heterogeneity also poses a diagnostic challenge. Using a next-generation sequencing-based multi-gene panel, we performed retrospective analysis of 98 pediatric patients who presented with advanced cholestatic liver disease. A likely causal mutation was identified in the majority (61%), spanning many genes including ones that have only rarely been reported to cause cholestatic liver disease, e.g. TJP2 and VIPAS39. We find no evidence to support mono-allelic phenotypic expression in the carrier parents despite the severe nature of the respective mutations, and no evidence of oligogenicity. The high-carrier frequency of the founder mutations identified in our cohort (1 in 87) suggests a minimum incidence of 1:7246, an alarmingly high disease burden that calls for the primary prevention through carrier screening.

Age determination in subadults using histological analysis of bones / Determinación de la edad en subadultos usando análisis histológico de los huesos

Abstract Introduction: According to the literature, the amount of osteons has been suggested as a good proxy to determine the age of death in adults. However in subadults research has not been carried out yet. Objective: To determine the accuracy of the histomorphometric technique predicting the age at death in subadults using bone remains. Methodology: The information of static histomorphometric parameters from about 120 iliac bones retrieved from the exhumed remains of subadults whose age at death was known was taken from the Granada collection. In order to predict the age at death we performed a step by step linear regression to estimate the fittest model. Results: The most closely and significantly associated biopsy findings with age were: the osteon count, the internal cortical width, and the trabecular bone volume. Pearson's correlation index indicated a weak linear association among these variables. To assess the accuracy of the model we used a coefficient of determination with a 0.32 value. 32% of the age variation in the subadults was explained by the three variables. Conclusion: This regression model explains a percentage of the total age variation in the subadult population. However this model is not enough to determine the age at death.

Resumen Introducción: La capacidad de predicción de las osteonas para determinar la edad de muerte de los individuos ha sido descrito en la literatura científica. No obstante, no se ha determinado dicha capacidad en individuos subadultos. Objetivo: Determinar la eficacia de lo parámetros histomorfometricos en población subadulta. Metodología: Se realizaron biopsias de hueso ilíaco en los restos de 120 subadultos, de la Colección Osteológica de Granada, con edad conocida en el momento de la muerte. Para establecer la capacidad de predicción se utilizó el R2 obtenido a partir de regresión lineal múltiple. Resultados: Las variables con mayor nivel predictivo y significativo para la estimación de la edad fueron: recuento de osteonas tipo 2 de la cortical interna y externa, y el volumen óseo trabecular; En la evaluación del modelo, se obtuvo un coeficiente de determinación de 0.32, es decir, el 32% de la variación en la edad de los subadultos se explica por el modelo. Sin embargo, se evidenció diferencias en la capacidad de predicción por sexo. Conclusión: Este modelo de regresión explica un porcentaje sustancial de la varianza de la edad de los individuos en la muestra. No obstante, no es suficiente para garantizar una adecuada predicción de la edad al momento de muerte de los individuos subdultos.