MED13L-related intellectual disability: involvement of missense variants and delineation of the phenotype.

Molecular anomalies in MED13L, leading to haploinsufficiency, have been reported in patients with moderate to severe intellectual disability (ID) and distinct facial features, with or without congenital heart defects. Phenotype of the patients was referred to "MED13L haploinsufficiency syndrome." Missense variants in MED13L were already previously described to cause the MED13L-related syndrome, but only in a limited number of patients. Here we report 36 patients with MED13L molecular anomaly, recruited through an international collaboration between centers of expertise for developmental anomalies. All patients presented with intellectual disability and severe language impairment. Hypotonia, ataxia, and recognizable facial gestalt were frequent findings, but not congenital heart defects. We identified seven de novo missense variations, in addition to protein-truncating variants and intragenic deletions. Missense variants clustered in two mutation hot-spots, i.e., exons 15-17 and 25-31. We found that patients carrying missense mutations had more frequently epilepsy and showed a more severe phenotype. This study ascertains missense variations in MED13L as a cause for MED13L-related intellectual disability and improves the clinical delineation of the condition.

Lorentz Symmetry Violations from Matter-Gravity Couplings with Lunar Laser Ranging.

The standard-model extension (SME) is an effective field theory framework aiming at parametrizing any violation to the Lorentz symmetry (LS) in all sectors of physics. In this Letter, we report the first direct experimental measurement of SME coefficients performed simultaneously within two sectors of the SME framework using lunar laser ranging observations. We consider the pure gravitational sector and the classical point-mass limit in the matter sector of the minimal SME. We report no deviation from general relativity and put new realistic stringent constraints on LS violations improving up to 3 orders of magnitude previous estimations.

Testing Lorentz Symmetry with Lunar Laser Ranging.

Lorentz symmetry violations can be parametrized by an effective field theory framework that contains both general relativity and the standard model of particle physics called the standard-model extension (SME). We present new constraints on pure gravity SME coefficients obtained by analyzing lunar laser ranging (LLR) observations. We use a new numerical lunar ephemeris computed in the SME framework and we perform a LLR data analysis using a set of 20 721 normal points covering the period of August, 1969 to December, 2013. We emphasize that linear combination of SME coefficients to which LLR data are sensitive and not the same as those fitted in previous postfit residuals analysis using LLR observations and based on theoretical grounds. We found no evidence for Lorentz violation at the level of 10^{-8} for s[over ¯]^{TX}, 10^{-12} for s[over ¯]^{XY} and s[over ¯]^{XZ}, 10^{-11} for s[over ¯]^{XX}-s[over ¯]^{YY} and s[over ¯]^{XX}+s[over ¯]^{YY}-2s[over ¯]^{ZZ}-4.5s[over ¯]^{YZ}, and 10^{-9} for s[over ¯]^{TY}+0.43s[over ¯]^{TZ}. We improve previous constraints on SME coefficient by a factor up to 5 and 800 compared to postfit residuals analysis of respectively binary pulsars and LLR observations.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

A French collaborative survey of 272 fetuses with 22q11.2 deletion: ultrasound findings, fetal autopsies and pregnancy outcomes.

OBJECTIVE: The 22q11.2 deletion (del22q11.2) is one of the most common microdeletions. We performed a collaborative, retrospective analysis in France of prenatal diagnoses and outcomes of fetuses carrying the del22q11.2. METHODS: A total of 272 fetuses were included. Data on prenatal diagnosis, ultrasound findings, pathological features, outcomes and inheritance were analyzed. RESULTS: The mean time of prenatal diagnosis was 25.6 ± 6 weeks of gestation. Most of the diagnoses (86.8%) were prompted by abnormal ultrasound findings [heart defects (HDs), in 83.8% of cases]. On fetal autopsy, HDs were again the most common disease feature, but thymus, kidney abnormalities and facial dysmorphism were also described. The deletion was inherited in 27% of cases. Termination of pregnancy (TOP) occurred in 68.9% of cases and did not appear to depend on the inheritance status. However, early diagnosis was associated with a higher TOP rate. CONCLUSION: This is the largest cohort of prenatal del22q11.2 diagnoses. As in postnatally diagnosed cases, HDs were the most frequently observed abnormalities. However, thymus and kidney abnormalities and polyhydramnios should also be screened for in the prenatal diagnosis of del22q11.2. Only the time of diagnosis appeared to be strongly associated with the pregnancy outcome: the earlier the diagnosis, the higher the TOP rate.

Trisomy 7 mosaicism prenatally misdiagnosed and maternal uniparental disomy in a child with pigmentary mosaicism and Russell- Silver syndrome.

Prenatal diagnosis of true mosaic trisomy 7 is rare in amniotic fluid and can be misinterpreted as pseudomosaic. The phenotype is highly variable and may be modified by a maternal uniparental disomy of chromosome 7 leading to mild Russell-Silver syndrome (RSS). We report here the third postnatal case of mosaic trisomy 7 with maternal uniparental disomy of chromosome 7 in a boy presenting a mild RSS. Fetal karyotype performed in amniocentesis for intrauterine growth retardation was considered normal. Mosaic trisomy 7 was diagnosed after birth, on fibroblasts karyotype performed for blaschkolinear pigmentary skin anomalies and failure to thrive. Maternal uniparental disomy of chromosome 7 was observed in blood sample. Retrospectively, trisomic 7 cells were identified in one prenatal long-term flask culture revealing a prenatal diagnosis failure. This report emphasizes the difficulty of assessing fetal mosaicism and distinguishing it from pseudomosaicism in cultured amniocytes. It is important to search for uniparental disomy as an indirect clue of trisomy 7 mosaicism and a major prognosis element. Although there are only few prenatal informative cases, detection of trisomy 7 in amniocentesis appears to be associated with a relatively good outcome when maternal uniparental disomy has been ruled out.

What can we learn from old microdeletion syndromes using array-CGH screening?

Most microdeletion syndromes identified before the implementation of array-comparative genomic hybridization (array-CGH) were presumed to be well-defined clinical entities. However, the introduction of whole-genome screening led not only to the description of new syndromes but also to the recognition of a broader spectrum of features for well-known syndromes. Here, we report on 10 patients presenting with mental retardation associated with atypical features not suggestive of a known microdeletion and a normal standard karyotype. Array-CGH analyses revealed five microdeletions in the DiGeorge region, three microdeletions in the Williams-Beuren region and two microdeletions in the Smith-Magenis region. Reevaluation in these patients confirmed that the diagnosis remained difficult on clinical grounds and emphasized that well-known genomic disorders can have a phenotype that is heterogeneous and more variable than originally thought. The widespread use of array-CGH shows that such patients may be more readily achieved on the basis of genotype rather than phenotype.

Preparation of new ß-D-xyloside- and ß-D-xylobioside-based ionic liquids through chemical and/or enzymatic reactions.

Several tetraalkylphosphonium and tetraalkylammonium salts containing xyloside- and xylobioside-based anionic moieties have been prepared. Two stereoselective routes have been developed: i) a chemical pathway in four steps from D-xylose, and ii) a chemoenzymatic pathway directly from biomass-derived xylans. These salts displayed interesting properties as ionic liquids. Their structures have been correlated to their thermal properties (melting, glass transition and decomposition temperatures).

[Birth of a child with Down syndrome: parental choice or failure of screening policy?]. / Naissance d'un enfant porteur de trisomie 21: choix parental ou défaut de la politique de dépistage ?

OBJECTIVES: Birth of a child with Down syndrome (DS) can follow parental choice or failure of screening. The objective of this work is to describe the circumstances of births of children with DS in a French perinatal health network. METHODS: Retrospective multicentric study, with prospective trial registration of all children born alive with DS, between 2010 and 2013. RESULTS: Sixty-three children were born with DS. Complete screening was performed by 61 % of patients, incomplete screening by 29 % of patients and no screening test by 10 %. Among these births, 50 % occurred following parental choice, 40 % following failure of screening and for 10 %, parental choice concerning screening was unknown. False negative had often calculating risk close to 1/1000. CONCLUSION: In this study, the birth of a child with DS occurred following parental choice in half of cases. It's necessary, to optimize the follow-up, to document in medical records the medical information and parental choice concerning DS screening and data of screening when this was done.

Synthesis, characterization and biodistribution of a new technetium-99m complex with trimethylsilylmethylisonitrile. Comparison with 99mTc-TBI and 99mTc-MIBI.

An isonitrile ligand with a silicium component was synthesized and a copper salt of this ligand was then used to form a 99mTc complex. We evaluated the physicochemical characteristics of the complex and its biodistribution in rat. The chemical properties, i.e. lipophilic affinity and charge, were comparable to those of other 99mTc complexes formed with similar isonitrile compounds (99mTc-MIBI and 99mTc-TBI). In contrast, the tissue biodistribution of this new technetium complex differed markedly, as it was mainly taken up in the liver and not at all in the heart.

Synthesis and biological evaluation of new diisocyanide- and triisocyanide-99mTc complexes.

This paper describes the synthesis of four new polyisocyanides (three diisocyanides and one triisocyanide). The complexation of 99mTc with these ligands is also studied through chromatography and revealed the formation of hexacoordinated 99mTc+1 complexes. Finally, biodistributions of these complexes in mice are given and compared. Heart captations are lower than the ones with [99mTc(MIBI)6]+ but remain constant and a satisfactory lungs clearance, probably due to the metabolization of the ligands, is observed.

Encapsulation of contrast imaging agents by polypropyleneimine-based dendrimers.

Polypropyleneimines (PPIs) functionalized by glycerol-based entities are prepared and characterized by diffusion-ordered spectroscopy NMR. Showing low cytotoxicity against MRC5 fibroblasts, their encapsulation capacities of gadolinium complexes was evaluated. T(1) measurements were performed to determine the relaxivity of the encapsulated gadopentetate dimeglumine (GdBOPTA) in dendrimers of fourth and fifth generation (GD-PPI-4 and GD-PPI-5). Comparison of the GdBOPTA relaxivity and the relaxivity of GdBOPTA-loaded dendrimers showed a slight increase of the gadolinium chelate relaxivity.

[Pseudohypoaldosteronisme type I: a rare cause of failure to thrive]. / Une cause rare de stagnation pondérale à la naissance : le pseudohypoaldostéronisme de type I.

We report on a boy, born on term, presenting with a weight loss and a persistent failure to thrive after 10 days despite a normal behavior under bottle-feeding. The clinical examination was normal and biological assessment revealed hyponatremia with hyponatriuria, normal kaliemia and elevated aldosterone values, leading to type I pseudohypoaldosteronism diagnosis. Treatment with salt supplementation allowed growth improvement. The diagnosis was confirmed by the identification of a mutation in the mineralocorticoid receptor. This change was also found in several family members.