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Context Idiopathic central precocious puberty (iCPP) is defined by the premature reactivation of the hypothalamic-pituitary-gonadal axis with normal magnetic resonance imaging scan of the central nervous system, causing the development of secondary sexual characteristics before age 8 years in girls and 9 years in boys. MKRN3 loss of function variants now represent the most common genetic cause of iCPP. Objective This work aims to document the clinical course of puberty in 8 families harboring pathogenic MKRN3 variants. Methods This is an observational case series study of patients with CPP due to MKRN3 variants followed in a single center. Results Genetic analysis of MKRN3 was carried out in 28 unrelated patients with iCPP and a family history of paternal inheritance or no/unavailable maternal inheritance, particularly in case of very early and rapidly evolving CPP. We identified 6 novel and 2 recently described variants in the MKRN3 gene in 9 girls, 1 boy, and their family members. These mutations were all predicted to be deleterious by in silico prediction programs Conclusion We have identified 6 novel MKRN3 mutations in children with CPP. An MKRN3 loss of function should be considered after careful history pinpointing paternally inherited CPP. A family segregation study allowed the detection of an MKRN3 variant in 2 young brothers still prepubertal, raising the question of screening and management of asymptomatic prepubertal family members. [ABSTRACT FROM AUTHOR]

We used a candidate gene approach to identify a set of SNPs, located in a predicted regulatory region on chromosome 1q44 downstream of NLRP3 (previously known as CIAS1 and NALP3) that are associated with Crohn's disease. The associations were consistently replicated in four sample sets from individuals of European descent. In the combined analysis of all samples (710 father-mother-child trios, 239 cases and 107 controls), these SNPs were strongly associated with risk of Crohn's disease (Pcombined = 3.49 × 10−9, odds ratio = 1.78, confidence interval = 1.47–2.16 for rs10733113), reaching a level consistent with the stringent significance thresholds imposed by whole-genome association studies. In addition, we observed significant associations between SNPs in the associated regions and NLRP3 expression and IL-1β production. Mutations in NLRP3 are known to be responsible for three rare autoinflammatory disorders. These results suggest that the NLRP3 region is also implicated in the susceptibility of more common inflammatory diseases such as Crohn's disease. [ABSTRACT FROM AUTHOR]

Since January 2020, neonatal screening for cystic fibrosis (CF-NBS) has been implemented in the Wallonia-Brussels Federation. It's based on the immunoreactive trypsin (IRT1) assay between day 2 and day 4, associated with a 12 CFTR pathogenic variants analysis and with an IRT control on day 21. The aim of this study is to evaluate the performance of our CF-NBS in Liège according to the quality criteria defined by the European Cystic Fibrosis Society's working group on neonatal screening. After four years, 58.762 newborns have been screened. Nineteen children with cystic fibrosis were diagnosed : 14 by NBS, 3 following a meconium ileus, 1 by family history and 1 false negative diagnosed on clinical basis. Furthermore, 39 healthy carriers and 2 uncertain diagnosis (CFSPID) were identified. The sensitivity of CF NBS is 93,3 % (target ≥ 95 %), the positive predictive value (PPV) 17,7 % (target ≥ 30 %). Increasing the TIR1 threshold by 0,1 in 0,1 from P99 to P99,5, would be associated with a lower sensitivity and a non-significant improvement of PPV. A national assessment of CF NBS needs to be carried out.

It is estimated that in highly medicalised countries, median life expectancy for most newborns with cystic fibrosis now exceeds 70 years, approaching that of the general population. However, socio-economic disparities between countries continue to have a devastating impact on the prognosis of patients in Eastern Europe, Africa, India and South America. In Morocco, very limited genetic data suggest that the prevalence of this disease is at least of the same order as in Belgium. But as it is not really recognised by the national health system, patients are denied access even to symptomatic treatment. As a result, their outcome is tragic, similar to what it was 60 years ago in the most medicalised countries. A pilot project for a first paediatric reference centre in Casablanca is currently being set up. If properly resourced, this project can only be a success and should be the first step on the road towards cystic fibrosis care in this country. In a very humble way, several Belgian stakeholders are trying to support this project.

Genome-wide association studies (GWAS) have identified dozens of risk loci for many complex disorders, including Crohn's disease. However, common disease-associated SNPs explain at most ∼20% of the genetic variance for Crohn's disease. Several factors may account for this unexplained heritability, including rare risk variants not adequately tagged thus far in GWAS. That rare susceptibility variants indeed contribute to variation in multifactorial phenotypes has been demonstrated for colorectal cancer, plasma high-density lipoprotein cholesterol levels, blood pressure, type 1 diabetes, hypertriglyceridemia and, in the case of Crohn's disease, for NOD2 (refs. 14,15). Here we describe the use of high-throughput resequencing of DNA pools to search for rare coding variants influencing susceptibility to Crohn's disease in 63 GWAS-identified positional candidate genes. We identify low frequency coding variants conferring protection against inflammatory bowel disease in IL23R, but we conclude that rare coding variants in positional candidates do not make a large contribution to inherited predisposition to Crohn's disease.

The inflammatory bowel diseases (IBD) Crohn's disease and ulcerative colitis are common causes of morbidity in children and young adults in the western world. Here we report the results of a genome-wide association study in early-onset IBD involving 3,426 affected individuals and 11,963 genetically matched controls recruited through international collaborations in Europe and North America, thereby extending the results from a previous study of 1,011 individuals with early-onset IBD. We have identified five new regions associated with early-onset IBD susceptibility, including 16p11 near the cytokine gene IL27 (rs8049439, P = 2.41 x 10(-9)), 22q12 (rs2412973, P = 1.55 x 10(-9)), 10q22 (rs1250550, P = 5.63 x 10(-9)), 2q37 (rs4676410, P = 3.64 x 10(-8)) and 19q13.11 (rs10500264, P = 4.26 x 10(-10)). Our scan also detected associations at 23 of 32 loci previously implicated in adult-onset Crohn's disease and at 8 of 17 loci implicated in adult-onset ulcerative colitis, highlighting the close pathogenetic relationship between early- and adult-onset IBD.

Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.