An emerging, recognizable facial phenotype in association with mutations in GLI-similar 3 ( GLIS3 )

Neonatal diabetes and hypothyroidism (NDH) syndrome was first described in 2003 in a consanguineous Saudi Arabian family where two out of four siblings were reported to have presented with proportionate IUGR, neonatal non-autoimmune diabetes mellitus, severe congenital hypothyroidism, cholestasis, congenital glaucoma, and polycystic kidneys. Liver disease progressed to hepatic fibrosis. The renal disease was characterised by enlarged kidneys and multiple small cysts with deficient cortico-medullary junction differentiation and normal kidney function. There was minor facial dysmorphism (depressed nasal bridge, large anterior fontanelle, long philtrum) reported but no facial photographs were published. Mutations in the transcription factor GLI-similar 3 (GLIS3) gene in the original family and two other families were subsequently reported in 2006. All affected individuals had neonatal diabetes, congenital hypothyroidism but glaucoma and liver and kidney involvement were less consistent features. Detailed descriptions of the facial dysmorphism have not been reported previously. In this report, we describe the common facial dysmorphism consisting of bilateral low-set ears, depressed nasal bridge with overhanging columella, elongated, upslanted palpebral fissures, persistent long philtrum with a thin vermilion border of the upper lip in a cohort of seven patients with GLIS3 mutations and report the emergence of a distinct, probably recognisable facial gestalt in this group which evolves with age

Genetic aetiology of glycaemic traits: approaches and insights.

Glycaemic traits such as fasting and post-challenge glucose and insulin measures, as well as glycated haemoglobin (HbA1c), are used to diagnose and monitor diabetes. These traits are risk factors for cardiovascular disease even below the diabetic threshold, and their study can additionally yield insights into the pathophysiology of type 2 diabetes. To date, a diverse set of genetic approaches have led to the discovery of over 97 loci influencing glycaemic traits. In this review, we will focus on recent advances in the genetic aetiology of glycaemic traits, and the resulting biological insights. We will provide a brief overview of results ranging from common, to low- and rare-frequency variant-trait association studies, studies leveraging the diversity across populations, and studies harnessing the power of genetic and genomic approaches to gain insights into the biological underpinnings of these traits

Exome Sequencing and Genetic Testing for MODY

Context: Genetic testing for monogenic diabetes is important for patient care. Given the extensive genetic and clinical heterogeneity of diabetes, exome sequencing might provide additional diagnostic potential when standard Sanger sequencing-based diagnostics is inconclusive. Objective: The aim of the study was to examine the performance of exome sequencing for a molecular diagnosis of MODY in patients who have undergone conventional diagnostic sequencing of candidate genes with negative results. Research Design and Methods: We performed exome enrichment followed by high-throughput sequencing in nine patients with suspected MODY. They were Sanger sequencing-negative for mutations in the HNF1A, HNF4A, GCK, HNF1B and INS genes. We excluded common, non-coding and synonymous gene variants, and performed in-depth analysis on filtered sequence variants in a pre-defined set of 111 genes implicated in glucose metabolism. Results: On average, we obtained 45 X median coverage of the entire targeted exome and found 199 rare coding variants per individual. We identified 0–4 rare non-synonymous and nonsense variants per individual in our a priori list of 111 candidate genes. Three of the variants were considered pathogenic (in ABCC8, HNF4A and PPARG, respectively), thus exome sequencing led to a genetic diagnosis in at least three of the nine patients. Approximately 91% of known heterozygous SNPs in the target exomes were detected, but we also found low coverage in some key diabetes genes using our current exome sequencing approach. Novel variants in the genes ARAP1, GLIS3, MADD, NOTCH2 and WFS1 need further investigation to reveal their possible role in diabetes. Conclusion: Our results demonstrate that exome sequencing can improve molecular diagnostics of MODY when used as a complement to Sanger sequencing. However, improvements will be needed, especially concerning coverage, before the full potential of exome sequencing can be realized

Refinement of the critical genomic region for congenital hyperinsulinism in the Chromosome 9p deletion syndrome

Version 2; peer review: 3 approved. Available from F1000 Research via the DOI in this recordBackground: Large contiguous gene deletions at the distal end of the short arm of chromosome 9 result in the complex multi-organ condition chromosome 9p deletion syndrome. A range of clinical features can result from these deletions with the most common being facial dysmorphisms and neurological impairment. Congenital hyperinsulinism is a rarely reported feature of the syndrome with the genetic mechanism for the dysregulated insulin secretion being unknown. Methods: We studied the clinical and genetic characteristics of 12 individuals with chromosome 9p deletions who had a history of neonatal hypoglycaemia. Using off-target reads generated from targeted next-generation sequencing of the genes known to cause hyperinsulinaemic hypoglycaemia (n=9), or microarray analysis (n=3), we mapped the minimal shared deleted region on chromosome 9 in this cohort. Targeted sequencing was performed in three patients to search for a recessive mutation unmasked by the deletion. Results: In 10/12 patients with hypoglycaemia, hyperinsulinism was confirmed biochemically. A range of extra-pancreatic features were also reported in these patients consistent with the diagnosis of the Chromosome 9p deletion syndrome. The minimal deleted region was mapped to 7.2 Mb, encompassing 38 protein-coding genes. In silico analysis of these genes highlighted SMARCA2 and RFX3 as potential candidates for the hypoglycaemia. Targeted sequencing performed on three of the patients did not identify a second disease-causing variant within the minimal deleted region. Conclusions: This study identifies 9p deletions as an important cause of hyperinsulinaemic hypoglycaemia and increases the number of cases reported with 9p deletions and hypoglycaemia to 15 making this a more common feature of the syndrome than previously appreciated. Whilst the precise genetic mechanism of the dysregulated insulin secretion could not be determined in these patients, mapping the deletion breakpoints highlighted potential candidate genes for hypoglycaemia within the deleted region.Wellcome TrustRoyal Societ

The New State Postconviction

I argue in this paper that, because Maples and Martinez coincide with other important developments that make state postconviction more important, they could have critical synergistic effects. Maples and Martinez create incentive for states to provide effective counsel in state postconviction at a moment when these proceedings are being forced to assume a new role in the development of federal constitutional criminal procedure. The confluence of these events could produce a new era in state postconviction

The New State Postconviction

This Article examines two October Term 2011 Supreme Court cases – Maples v. Thomas and Martinez v. Ryan – which have a significant impact on the provision of counsel in state postconviction proceedings. In Maples and Martinez the Court expanded the circumstances in which deficient performance by state postconviction counsel can overcome procedural default, to permit the prisoner to litigate defaulted claims on the merits in federal habeas. The Author argues that, given the increased significance of state postconviction under the Anti-Terrorism and Effective Death Penalty Act (AEDPA), Maples and Martinez could have a salutary effect on the development of the federal constitutional criminal procedure litigated in those proceedings. Furthermore, because these cases coincide with other important developments that make state postconviction more important, they could have critical synergistic effects. Maples and Martinez create incentive for states to provide effective counsel in state postconviction at a moment when these proceeding are being forced to assume a new role in the development of federal constitutional criminal procedure. The confluence of these events could produce a new era in state postconviction

Personalized bone reconstruction and regeneration in the treatment of craniosynostosis

Craniosynostosis (CS) is the second most prevalent craniofacial congenital malformation due to the premature fusion of skull sutures. CS care requires surgical treatment of variable complexity, aimed at resolving functional and cosmetic defects resulting from the skull growth constrain. Despite significant innovation in the management of CS, morbidity and mortality still exist. Residual cranial defects represent a potential complication and needdedicated management to drive a targeted bone regeneration while modulating suture ossification. To this aim, existing techniques are rapidly evolving and include the implementation of novel biomaterials, 3D printing and additive manufacturing techniques, and advanced therapies based on tissue engineering. This review aims at providing an exhaustive and up\u2010to\u2010date overview of the strategies in use to correct these congenital defects, focusing on the technological advances in the fields of biomaterials and tissue engineering implemented in pediatric surgical skull reconstruction, i.e., biodegradable bone fixation systems, biomimetic scaffolds, drug delivery systems, and cell\u2010based approaches

PIM place & ghost application

Actualment, el Servei d'Informàtica de l'Escola d'Enginyeries (SIEE) s'enfronta a dos problemes: l'augment del nombre d'alumnes, mantenint el mateix número d'ordinadors per fer les pràctiques i, d'altra banda, el també creixent nombre d'aplicacions que s'han desenvolupat i es desenvolupen per resoldre les necessitats generades pels mateixos alumnes. Aquest projecte neix amb la voluntat de solucionar aquests problemes, creant per un costat un aula de màquines virtuals i per altra banda crear un aplicatiu web, que servirà de framework i contenidor de futures aplicacions, on es pugui connectar de manera senzilla amb les màquines virtuals.Actualmente, el Servicio de Informática de la Escuela de Ingenierias (SIEE) se enfrenta a dos problemas: el aumento del número de alumnos, manteniendo el mismo número de ordenadores para hacer las pràcticas y, por otro lado, el también creciente número de aplicaciones que se han desarrollado y se desarrollan para resolver las necesidades generadas por estos mismos alumnos. Este proyecto nace con la voluntad de solucionar estos problemas, creando por un lado un aula de máquinas virtuales y por otra parte crear una aplicación web, que servirá de framework y contenedor de futuras aplicaciones, donde se pueda conectar de manera sencilla con las máquinas virtuales.Now, the computer service of the engineering school (SIEE) faced two problems: the increase of the number of the students keeping the same number of computers to do the practise and, for the other side, the increase of the number of applications developed and that are developing to resolve the needs generated by the students. This project born with the wish of solve this problems, make a classroom of virtuals machines and for other side make a web application, that use it of framework and container of future application, where the student can connect in a simply way with the virtual machines

Monogenic Diabetes: Implementation of translational genomic research towards precision medicine.

Various forms of early-onset non-autoimmune diabetes are recognized as monogenic diseases, each subtype being caused by a single highly penetrant gene defect at the individual level. Monogenic diabetes (MD) is clinically and genetically heterogeneous, including maturity-onset diabetes of the young (MODY), infancy-onset and neonatal diabetes mellitus, which are characterized by functional defects of insulin-producing pancreatic β-cells and hyperglycemia early in life. Depending on the genetic cause, MD differs in ages at diabetes onset, the severity of hyperglycemia, long-term diabetic complications and extra-pancreatic manifestations. In this review, we discuss the many challenges of molecular genetic diagnosis of MD in the face of a substantial genetic heterogeneity; as well as the clinical benefit and cost-effectiveness of an early genetic diagnosis as demonstrated by simulation models based on lifetime complications and treatment costs. We also discuss striking examples of proof-of-concept of genomic medicine, which enabled to remarkably improve patients' care and long-term evolution. Recent advances in genome editing and pluripotent stem-cell reprogramming technologies provide new opportunities for in vitro diabetes modelling and the discovery of novel drug targets and cell-based diabetes therapies. A review of these future directions makes the case for exciting translational research for further understanding early-onset diabetes pathophysiology

Diabetes mellitus associated genetic syndromes

La diabetes mellitus se reconoce como conjunto de trastornos heterogéneos que tiene como elemento común la hiperglucemia persistente. Aunque las formas más frecuentes de diabetes mellitus (DM), las tipo 1 y 2, son poligénicas, cada vez conocemos más formas monogénicas, cuya prevalencia se estima en 2-5 % de todos los pacientes con diabetes. Las formas monogénicas se puede clasificar en no Sindrómicas y Sindrómicas. Hay más de 80 diferentes síndromes genéticos asociados con intolerancia a la glucosa y en algunos casos con diabetes clínica. Estos síndromes nos han enseñado que las mutaciones en muchos loci diferentes pueden producir alteraciones en el metabolismo de la glucosa. Los podemos agrupar en Síndromes asociados con la degeneración pancreática, Diabetes neonatal sin alteración pancreática, Errores innatos del metabolismo asociados a DM, Enfermedades neuromusculares asociadas a DM, Síndromes de envejecimiento asociados a DM, Enfermedades Mitocondriales con DM, Síndromes genéticos con lipodistrofia asociados a DM, y otros. El objetivo de esta revisión es describir el mayor número posible de estos síndromes genéticos asociados a DM, para favorecer su reconocimiento, puesto que muchos presentan una serie de repercusiones relacionadas con el diagnóstico, complicaciones, tratamiento y pronóstico. Igualmente esto posibilitará el manejo específico de cada caso y el asesoramiento dirigido para los pacientes que presentan DM asociada a un espectro amplio de anomalías.Artículo de revisión60-77Diabetes is recognized as a heterogeneous group of disorders presenting hperglycemia and glucose intolerance as common elements. Although the most common forms of diabetes mellitus (DM) type 1 and 2 are polygenic, there are also many different types of monogenic forms; the prevalence of these monogenic forms is estimated at 2-5% of all patients with diabetes. These types of diabetes can be divided into syndromic and non-syndromic. There are over 80 different genetic syndromes associated with glucose intolerance, and in some patients with clinical diabetes. From these syndromes we learn that mutations at many different loci can cause glucose intolerance. They can be grouped in syndromes associated with pancreatic degeneration, neonatal diabetes without pancreatic disorder, innate errors of metabolism associated with DM, neuromuscular diseases associated with DM, Syndromes of aging associated with DM, Mitochondrial Diseases associated with DM, Genetic syndromes with lipodystrophy associated with DM and Others. The objective of this review is to describe many of these genetic syndromes associated with diabetes, to help the clinician to recognize them, given that they present differential characteristics, complications, therapeutical implications and different prognosis related with the diagnosis. This identification will also allow a directed management for each case and the advice for patients who have DM associated with a wide spectrum of abnormalities