Constitutively active Lyn kinase causes a cutaneous small vessel vasculitis and liver fibrosis syndrome

Neutrophilic inflammation is a hallmark of many monogenic autoinflammatory diseases; pathomechanisms that regulate extravasation of damaging immune cells into surrounding tissues are poorly understood. Here we identified three unrelated boys with perinatal-onset of neutrophilic cutaneous small vessel vasculitis and systemic inflammation. Two patients developed liver fibrosis in their first year of life. Next-generation sequencing identified two de novo truncating variants in the Src-family tyrosine kinase, LYN, p.Y508*, p.Q507* and a de novo missense variant, p.Y508F, that result in constitutive activation of Lyn kinase. Functional studies revealed increased expression of ICAM-1 on induced patient-derived endothelial cells (iECs) and of β2-integrins on patient neutrophils that increase neutrophil adhesion and vascular transendothelial migration (TEM). Treatment with TNF inhibition improved systemic inflammation; and liver fibrosis resolved on treatment with the Src kinase inhibitor dasatinib. Our findings reveal a critical role for Lyn kinase in modulating inflammatory signals, regulating microvascular permeability and neutrophil recruitment, and in promoting hepatic fibrosis

Correlation between genetic and geographic structure in Europe

Understanding the genetic structure of the European population is important, not only from a historical perspective, but also for the appropriate design and interpretation of genetic epidemiological studies. Previous population genetic analyses with autosomal markers in Europe either had a wide geographic but narrow genomic coverage [1, 2], or vice versa [3-6]. We therefore investigated Affymetrix GeneChip 500K genotype data from 2,514 individuals belonging to 23 different subpopulations, widely spread over Europe. Although we found only a low level of genetic differentiation between subpopulations, the existing differences were characterized by a strong continent-wide correlation between geographic and genetic distance. Furthermore, mean heterozygosity was larger, and mean linkage disequilibrium smaller, in southern as compared to northern Europe. Both parameters clearly showed a clinal distribution that provided evidence for a spatial continuity of genetic diversity in Europe. Our comprehensive genetic data are thus compatible with expectations based upon European population history, including the hypotheses of a south-north expansion and/or a larger effective population size in southern than in northern Europe. By including the widely used CEPH from Utah (CEU) samples into our analysis, we could show that these individuals represent northern and western Europeans reasonably well, thereby confirming their assumed regional ancestry

An evaluation of the genetic matched pair study design using genome-wide SNP data from the European population

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A European consensus for the evaluation and management of infants with an equivocal diagnosis following newborn screening for cystic fibrosis

Screening newborns for cystic fibrosis (CF) is considered to be an ethical undertaking in regions with a significant incidence of the condition. Current screening protocols result in recognition of infants with an equivocal diagnosis. A survey of European practice suggested inconsistencies in the evaluation and management of these infants. We have undertaken a consensus process using a modified Delphi method. This has enabled input of CF specialists from a wide geographical area to a rigorous process that has provided a clear pathway to a consensus statement. A core group produced 21 statements, which were modified over a series of three rounds (including a meeting arranged at the European CF Conference). A final document of 19 statements was produced, all of which achieved a satisfactory level of consensus. The statements cover four themes; sweat testing, further assessments and investigations, review arrangements and database. This consensus document will provide guidance to CF specialists with established screening programmes and those who are in the process of implementing newborn screening in their region