Differential dysregulation of granule subsets in WASH-deficient neutrophil leukocytes resulting in inflammation.

Dysregulated secretion in neutrophil leukocytes associates with human inflammatory disease. The exocytosis response to triggering stimuli is sequential; gelatinase granules modulate the initiation of the innate immune response, followed by the release of pro-inflammatory azurophilic granules, requiring stronger stimulation. Exocytosis requires actin depolymerization which is actively counteracted under non-stimulatory conditions.

Moment estimators of relatedness from low-depth whole-genome sequencing data.

Background: Estimating relatedness is an important step for many genetic study designs. A variety of methods for estimating coefficients of pairwise relatedness from genotype data have been proposed. Both the kinship coefficient [Formula: see text] and the fraternity coefficient [Formula: see text] for all pairs of individuals are of interest.

ZBTB2 protein is a new partner of the Nucleosome Remodeling and Deacetylase (NuRD) complex.

ZBTB2 is a protein belonging to the BTB/POZ zinc-finger family whose members typically contain a BTB/POZ domain at the N-terminus and several zinc-finger domains at the C-terminus. Studies have been carried out to disclose the role of ZBTB2 in cell proliferation, in human cancers and in regulating DNA methylation. Moreover, ZBTB2 has been also described as an ARF, p53 and p21 gene repressor as well as an activator of genes modulating pluripotency.

Associations of autozygosity with a broad range of human phenotypes.

In many species, the offspring of related parents suffer reduced reproductive success, a phenomenon known as inbreeding depression. In humans, the importance of this effect has remained unclear, partly because reproduction between close relatives is both rare and frequently associated with confounding social factors. Here, using genomic inbreeding coefficients (F) for >1.

The Incontinentia Pigmenti Genetic Biobank: study design and cohort profile to facilitate research into a rare disease worldwide.

Incontinentia pigmenti (IP; OMIM#308300) is a rare genetic disease resulting in neuroectodermal defects, which can lead to disability. At present, there is neither definitive cure available nor are there any sufficiently reliable insights to predict the severity of the disease. We launched the Incontinentia Pigmenti Genetic Biobank (IPGB) project ( http://www.

Whole-Exome Sequencing in the Isolated Populations of Cilento from South Italy.

The present study describes the genetic architecture of the isolated populations of Cilento, through the analysis of exome sequence data of 245 representative individuals of these populations. By annotating the exome variants and cataloguing them according to their frequency and functional effects, we identified 347,684 variants, 67.4% of which are rare and low frequency variants, and 1% of them (corresponding to 319 variants per person) are classified as high functional impact variants; also, 39,946 (11.

Detecting the dominance component of heritability in isolated and outbred human populations.

Inconsistencies between published estimates of dominance heritability between studies of human genetic isolates and human outbred populations incite investigation into whether such differences result from particular trait architectures or specific population structures. We analyse simulated datasets, characteristic of genetic isolates and of unrelated individuals, before analysing the isolate of Cilento for various commonly studied traits. We show the strengths of using genetic relationship matrices for variance decomposition over identity-by-descent based methods in a population isolate and that heritability estimates in isolates will avoid the downward biases that may occur in studies of samples of unrelated individuals; irrespective of the simulated distribution of causal variants.

Expert consensus document: Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement.

Beckwith-Wiedemann syndrome (BWS), a human genomic imprinting disorder, is characterized by phenotypic variability that might include overgrowth, macroglossia, abdominal wall defects, neonatal hypoglycaemia, lateralized overgrowth and predisposition to embryonal tumours. Delineation of the molecular defects within the imprinted 11p15.5 region can predict familial recurrence risks and the risk (and type) of embryonal tumour.

Strategies for phasing and imputation in a population isolate.

In the search for genetic associations with complex traits, population isolates offer the advantage of reduced genetic and environmental heterogeneity. In addition, cost-efficient next-generation association approaches have been proposed in these populations where only a subsample of representative individuals is sequenced and then genotypes are imputed into the rest of the population. Gene mapping in such populations thus requires high-quality genetic imputation and preliminary phasing.

Genome-wide meta-analysis associates HLA-DQA1/DRB1 and LPA and lifestyle factors with human longevity.

Genomic analysis of longevity offers the potential to illuminate the biology of human aging. Here, using genome-wide association meta-analysis of 606,059 parents' survival, we discover two regions associated with longevity (HLA-DQA1/DRB1 and LPA). We also validate previous suggestions that APOE, CHRNA3/5, CDKN2A/B, SH2B3 and FOXO3A influence longevity.

Assisted Reproductive Techniques and Risk of Beckwith-Wiedemann Syndrome.

Background And Objectives: The emerging association of assisted reproductive techniques (ART) with imprinting disorders represents a major issue in the scientific debate on infertility treatment and human procreation. We studied the prevalence of Beckwith-Wiedemann syndrome (BWS) in children conceived through ART to define the specific associated relative risk.

Methods: Patients with BWS born in Piemonte, Italy, were identified and matched with the general demographic data and corresponding regional ART registry.

Fetal growth patterns in Beckwith-Wiedemann syndrome.

We provide data on fetal growth pattern on the molecular subtypes of Beckwith-Wiedemann syndrome (BWS): IC1 gain of methylation (IC1-GoM), IC2 loss of methylation (IC2-LoM), 11p15.5 paternal uniparental disomy (UPD), and CDKN1C mutation. In this observational study, gestational ages and neonatal growth parameters of 247 BWS patients were compared by calculating gestational age-corrected standard deviation scores (SDS) and proportionality indexes to search for differences among IC1-GoM (n = 21), UPD (n = 87), IC2-LoM (n = 147), and CDKN1C mutation (n = 11) patients.

Recommendations of the Scientific Committee of the Italian Beckwith-Wiedemann Syndrome Association on the diagnosis, management and follow-up of the syndrome.

Unlabelled: Beckwith-Wiedemann syndrome (BWS) is the most common (epi)genetic overgrowth-cancer predisposition disorder. Given the absence of consensual recommendations or international guidelines, the Scientific Committee of the Italian BWS Association (www.aibws.

Meta-analysis of Genome-Wide Association Studies for Extraversion: Findings from the Genetics of Personality Consortium.

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts.

(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome: a paradigm for genomic medicine.

Beckwith-Wiedemann syndrome (BWS) is the commonest overgrowth cancer predisposition disorder and represents a model for human imprinting dysregulation and tumorigenesis. BWS features can variably combine and present a widely variable range of severity in the phenotypic expression. This wide spectrum is paralleled at molecular level by complex (epi)genetic defects on chromosome 11p15.

Experience-dependent DNA methylation regulates plasticity in the developing visual cortex.

DNA methylation is an epigenetic repressor mark for transcription dynamically regulated in neurons. We analyzed visual experience regulation of DNA methylation in mice and its involvement in ocular dominance plasticity of the developing visual cortex. Monocular deprivation modulated the expression of factors controlling DNA methylation and exerted opposite effects on DNA methylation and hydroxymethylation in specific plasticity genes.

Exploring the possible link between MeCP2 and oxidative stress in Rett syndrome.

Rett syndrome (RTT, MIM 312750) is a rare and orphan progressive neurodevelopmental disorder affecting girls almost exclusively, with a frequency of 1/15,000 live births of girls. The disease is characterized by a period of 6 to 18 months of apparently normal neurodevelopment, followed by early neurological regression, with a progressive loss of acquired cognitive, social, and motor skills. RTT is known to be caused in 95% of the cases by sporadic de novo loss-of-function mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene encoding methyl-CpG binding protein 2 (MeCP2), a nuclear protein able to regulate gene expression.

(Epi)genotype-phenotype correlations in Beckwith-Wiedemann syndrome.

Beckwith-Wiedemann syndrome (BWS) is characterized by cancer predisposition, overgrowth and highly variable association of macroglossia, abdominal wall defects, nephrourological anomalies, nevus flammeus, ear malformations, hypoglycemia, hemihyperplasia, and organomegaly. BWS molecular defects, causing alteration of expression or activity of the genes regulated by two imprinting centres (IC) in the 11p15 chromosomal region, are also heterogeneous. In this paper we define (epi)genotype-phenotype correlations in molecularly confirmed BWS patients.

17β-estradiol inhibits spreading of metastatic cells from granulosa cell tumors through a non-genomic mechanism involving GPER1.

Granulosa cell tumor (GCT) is a rare and severe form of sex-cord stromal ovarian tumor that is characterized by its long natural history and tendency to recur years after surgical ablation. Because there is no efficient curative treatment beyond surgery, ~20% of patients die of the consequences of their tumor. However, very little is known of the molecular etiology of this pathology.

Understanding gene regulatory mechanisms by integrating ChIP-seq and RNA-seq data: statistical solutions to biological problems.

The availability of omic data produced from international consortia, as well as from worldwide laboratories, is offering the possibility both to answer long-standing questions in biomedicine/molecular biology and to formulate novel hypotheses to test. However, the impact of such data is not fully exploited due to a limited availability of multi-omic data integration tools and methods. In this paper, we discuss the interplay between gene expression and epigenetic markers/transcription factors.

Salt-inducible kinase 3, SIK3, is a new gene associated with hearing.

Hearing function is known to be heritable, but few significant and reproducible associations of genetic variants have been identified to date in the adult population. In this study, genome-wide association results of hearing function from the G-EAR consortium and TwinsUK were used for meta-analysis. Hearing ability in eight population samples of Northern and Southern European ancestry (n = 4591) and the Silk Road (n = 348) was measured using pure-tone audiometry and summarized using principal component (PC) analysis.

Modulation of the pentose phosphate pathway induces endodermal differentiation in embryonic stem cells.

Embryonic stem (ES) cells can differentiate in vitro into a variety of cell types. Efforts to produce endodermal cell derivatives, including lung, liver and pancreas, have been met with modest success. Understanding how the endoderm originates from ES cells is the first step to generate specific cell types for therapeutic purposes.

Ochratoxin A induces craniofacial malformation in mice acting on Dlx5 gene expression.

Ochratoxin A (OTA) is a mycotoxin produced by fungal of Aspergillus species absorbed in human through contaminate food in gastrointestinal tract. OTA has been demonstrated to be teratogenic in a number of species including mice and potentially human. Mice exposed in uterus to OTA develop craniofacial abnormalities such as exencephaly, microencephaly, microphthalmia and facial clefts.

Maintenance of X- and Y-inactivation of the pseudoautosomal (PAR2) gene SPRY3 is independent from DNA methylation and associated to multiple layers of epigenetic modifications.

Maintenance of X-inactivation is achieved through a combination of different repressive mechanisms, thus perpetuating the silencing message through many cell generations. The second human X-Y pseudoautosomal region 2 (PAR2) is a useful model to explore the features and internal relationships of the epigenetic circuits involved in this phenomenon. Recently, we demonstrated that DNA methylation plays an essential role for the maintenance of X- and Y-inactivation of the PAR2 gene SYBL1; here we report that the silencing of the second repressed PAR2 gene, SPRY3, appears to be independent of DNA methylation.