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Strasbourg, France

Redin C.,University of Strasbourg | Redin C.,College de France | Gerard B.,Hopitaux Universitaires Of Strasbourg | Lauer J.,Hopitaux Universitaires Of Strasbourg | And 42 more authors.
Journal of Medical Genetics | Year: 2014

Background Intellectual disability (ID) is characterised by an extreme genetic heterogeneity. Several hundred genes have been associated to monogenic forms of ID, considerably complicating molecular diagnostics. Trio-exome sequencing was recently proposed as a diagnostic approach, yet remains costly for a general implementation. Methods We report the alternative strategy of targeted high-throughput sequencing of 217 genes in which mutations had been reported in patients with ID or autism as the major clinical concern. We analysed 106 patients with ID of unknown aetiology following array-CGH analysis and other genetic investigations. Ninety per cent of these patients were males, and 75% sporadic cases. Results We identified 26 causative mutations: 16 in X-linked genes (ATRX, CUL4B, DMD, FMR1, HCFC1, IL1RAPL1, IQSEC2, KDM5C, MAOA, MECP2, SLC9A6, SLC16A2, PHF8) and 10 de novo in autosomal-dominant genes (DYRK1A, GRIN1, MED13L, TCF4, RAI1, SHANK3, SLC2A1, SYNGAP1). We also detected four possibly causative mutations (eg, in NLGN3) requiring further investigations. We present detailed reasoning for assigning causality for each mutation, and associated patients' clinical information. Some genes were hit more than once in our cohort, suggesting they correspond to more frequent ID-associated conditions (KDM5C, MECP2, DYRK1A, TCF4). We highlight some unexpected genotype to phenotype correlations, with causative mutations being identified in genes associated to defined syndromes in patients deviating from the classic phenotype (DMD, TCF4, MECP2). We also bring additional supportive (HCFC1, MED13L) or unsupportive (SHROOM4, SRPX2) evidences for the implication of previous candidate genes or mutations in cognitive disorders. Conclusions With a diagnostic yield of 25% targeted sequencing appears relevant as a first intention test for the diagnosis of ID, but importantly will also contribute to a better understanding regarding the specific contribution of the many genes implicated in ID and autism. © 2014 by the BMJ Publishing Group Ltd. Source

Fischbach M.,CHU de Hautepierre | Fothergill H.,CHU de Hautepierre | Seuge L.,CHU de Hautepierre | Zaloszyc A.,CHU de Hautepierre
Journal of Renal Nutrition | Year: 2011

Despite major advances in the understanding and management of uremic growth failure, 35% to 50% of children with chronic kidney disease still grow up to become adults of small stature. The final adult height achieved is correlated with the height deficit recorded at the time of kidney transplantation. A degree of catch-up growth does occur after kidney transplantation in childhood, but it is often limited. Growth retardation in children with chronic kidney disease causes significant difficulties in their daily lives, often limiting psychosocial integration. Additionally, growth retardation is associated with a greater number of hospital admissions and an increased risk of mortality. Growth failure is the common endpoint of a variety of pathologies, including growth hormone resistance. In children on chronic dialysis, linear growth may be improved by ensuring that optimal clinical care is provided. This includes maximizing nutritional support (e.g., tube feeding in cases of anorexia) so as to prevent malnutrition. Further management options include the administration of recombinant human growth hormone (rhGH) treatment and the use of more frequent and intensive dialysis sessions, such as daily on-line hemodiafiltration, which combines increased dialysis convective flow with ultrapure dialysate, to limit cachexia. © 2011 National Kidney Foundation, Inc. Source

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