Titin truncating variants (TTNtv) commonly cause dilated cardiomyopathy (DCM). TTNtv are also encountered in ~1% of the general population where they may be silent, perhaps reflecting allelic factors. To better understand TTNtv we integrated TTN allelic series, cardiac imaging and genomic data in humans and studied rat models with disparate TTNtv. In patients with DCM, TTNtv throughout TTN were significantly associated with DCM. Ribosomal profiling in rat revealed the translational footprint of premature stop codons in Ttn, TTNtv position-independent nonsense-mediated degradation of the mutant allele and a signature of perturbed cardiac metabolism. Heart physiology in rats with TTNtv was unremarkable at baseline but became impaired during cardiac stress. In healthy humans, machine-based analysis of high-resolution cardiac scans showed TTNtv to be associated with eccentric cardiac remodelling. These data show that TTNtv have molecular and physiological effects on the heart across species, with a continuum of expressivity in health and disease.

Eczema often precedes the development of asthma in a disease course called the ‘atopic march'. To unravel the genes underlying this characteristic pattern of allergic disease, we conduct a multi-stage genome-wide association study on infantile eczema followed by childhood asthma in 12 populations including 2,428 cases and 17,034 controls. Here we report two novel loci specific for the combined eczema plus asthma phenotype, which are associated with allergic disease for the first time; rs9357733 located in EFHC1 on chromosome 6p12.3 (OR 1.27; P=2.1 × 10−8) and rs993226 between TMTC2 and SLC6A15 on chromosome 12q21.3 (OR 1.58; P=5.3 × 10−9). Additional susceptibility loci identified at genome-wide significance are FLG (1q21.3), IL4/KIF3A (5q31.1), AP5B1/OVOL1 (11q13.1), C11orf30/LRRC32 (11q13.5) and IKZF3 (17q21). We show that predominantly eczema loci increase the risk for the atopic march. Our findings suggest that eczema may play an important role in the development of asthma after eczema.

BackgroundGenetic variation is an important determinant of RNA transcription and splicing, which in turn contributes to variation in human traits, including cardiovascular diseases.ResultsHere we report the first in-depth survey of heart transcriptome variation using RNA-sequencing in 97 patients with dilated cardiomyopathy and 108 non-diseased controls. We reveal extensive differences of gene expression and splicing between dilated cardiomyopathy patients and controls, affecting known as well as novel dilated cardiomyopathy genes. Moreover, we show a widespread effect of genetic variation on the regulation of transcription, isoform usage, and allele-specific expression. Systematic annotation of genome-wide association SNPs identifies 60 functional candidate genes for heart phenotypes, representing 20% of all published heart genome-wide association loci. Focusing on the dilated cardiomyopathy phenotype we found that eQTL variants are also enriched for dilated cardiomyopathy genome-wide association signals in two independent cohorts.ConclusionsRNA transcription, splicing, and allele-specific expression are each important determinants of the dilated cardiomyopathy phenotype and are controlled by genetic factors. Our results represent a powerful resource for the field of cardiovascular genetics.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-017-1286-z) contains supplementary material, which is available to authorized users.

BackgroundThe aim of this study is to identify independent pre-transplant cancer risk factors after kidney transplantation and to assess the utility of G-chart analysis for clinical process control. This may contribute to the improvement of cancer surveillance processes in individual transplant centers.Patients and Methods1655 patients after kidney transplantation at our institution with a total of 9,425 person-years of follow-up were compared retrospectively to the general German population using site-specific standardized-incidence-ratios (SIRs) of observed malignancies. Risk-adjusted multivariable Cox regression was used to identify independent pre-transplant cancer risk factors. G-chart analysis was applied to determine relevant differences in the frequency of cancer occurrences.ResultsCancer incidence rates were almost three times higher as compared to the matched general population (SIR = 2.75; 95%-CI: 2.33–3.21). Significantly increased SIRs were observed for renal cell carcinoma (SIR = 22.46), post-transplant lymphoproliferative disorder (SIR = 8.36), prostate cancer (SIR = 2.22), bladder cancer (SIR = 3.24), thyroid cancer (SIR = 10.13) and melanoma (SIR = 3.08). Independent pre-transplant risk factors for cancer-free survival were age <52.3 years (p = 0.007, Hazard ratio (HR): 0.82), age >62.6 years (p = 0.001, HR: 1.29), polycystic kidney disease other than autosomal dominant polycystic kidney disease (ADPKD) (p = 0.001, HR: 0.68), high body mass index in kg/m2 (p<0.001, HR: 1.04), ADPKD (p = 0.008, HR: 1.26) and diabetic nephropathy (p = 0.004, HR = 1.51). G-chart analysis identified relevant changes in the detection rates of cancer during aftercare with no significant relation to identified risk factors for cancer-free survival (p<0.05).ConclusionsRisk-adapted cancer surveillance combined with prospective G-chart analysis likely improves cancer surveillance schemes by adapting processes to identified risk factors and by using G-chart alarm signals to trigger Kaizen events and audits for root-cause analysis of relevant detection rate changes. Further, comparative G-chart analysis would enable benchmarking of cancer surveillance processes between centers.

Table of contentsWORKSHOP 4: Challenging clinical scenarios (CS01–CS06)CS01 Bullous lesions in two children: solitary mastocytomaS. Tolga Yavuz, Ozan Koc, Ali Gungor, Faysal GokCS02 Multi-System Allergy (MSA) of cystic fibrosis: our institutional experienceJessica Hawley, Christopher O’Brien, Matthew Thomas, Malcolm Brodlie, Louise MichaelisCS03 Cold urticaria in pediatric age: an invisible cause for severe reactionsInês Mota, Ângela Gaspar, Susana Piedade, Graça Sampaio, José Geraldo Dias, Miguel Paiva, Mário Morais-AlmeidaCS04 Angioedema with C1 inhibitor deficiency in a girl: a challenge diagnosisCristina Madureira, Tânia Lopes, Susana Lopes, Filipa Almeida, Alexandra Sequeira, Fernanda Carvalho, José OliveiraCS05 A child with unusual multiple organ allergy disease: what is the primer?Fabienne Gay-CrosierCS06 A case of uncontrolled asthma in a 6-year-old patientIoana-Valentina Nenciu, Andreia Florina Nita, Alexandru Ulmeanu, Dumitru Oraseanu, Carmen ZapucioiuORAL ABSTRACT SESSION 1: Food allergy (OP01–OP06)OP01 Food protein-induced enterocolitis syndrome: oral food challenge outcomes for tolerance evaluation in a Pediatric HospitalAdrianna Machinena, Olga Domínguez Sánchez, Montserrat Alvaro Lozano, Rosa Jimenez Feijoo, Jaime Lozano Blasco, Mònica Piquer Gibert, Mª Teresa Giner Muñoz, Marcia Dias da Costa, Ana Maria Plaza MartínOP02 Characteristics of infants with food protein-induced enterocolitis syndrome and allergic proctocolitisEbru Arik Yilmaz, Özlem Cavkaytar, Betul Buyuktiryaki, Ozge Soyer, Cansin SackesenOP03 The clinical and immunological outcomes after consumption of baked egg by 1–5 year old egg allergic children: results of a randomised controlled trialMerrynNetting, Adaweyah El-Merhibi, Michael Gold, PatrickQuinn, IrmeliPenttila, Maria MakridesOP04 Oral immunotherapy for treatment of egg allergy using low allergenic, hydrolysed eggStavroula Giavi, Antonella Muraro, Roger Lauener, Annick Mercenier, Eugen Bersuch, Isabella M. Montagner, Maria Passioti, Nicolò Celegato, Selina Summermatter, Sophie Nutten, Tristan Bourdeau, Yvonne M. Vissers, Nikolaos G. PapadopoulosOP05 Chemical modification of a peanut extract results in an increased safety profile while maintaining efficacyHanneke van der Kleij, Hans Warmenhoven, Ronald van Ree, Raymond Pieters, Dirk Jan Opstelten, Hans van Schijndel, Joost SmitOP06 Administration of the yellow fever vaccine in egg allergic childrenRoisin Fitzsimons, Victoria Timms, George Du ToitORAL ABSTRACT SESSION 2: Asthma (OP07–OP12)OP07 Previous exacerbation is the most important risk factor for future exacerbations in school-age children with asthmaS. Tolga Yavuz, Guven Kaya, Mustafa Gulec, Mehmet Saldir, Osman Sener, Faysal GokOP08 Comparative study of degree of severity and laboratory changes between asthmatic children using different acupuncture modalitiesNagwa Hassan, Hala Shaaban, Hazem El-Hariri, Ahmed Kamel Inas E. MahfouzOP09 The concentration of exhaled carbon monoxide in asthmatic children with different controlled stadiumPapp Gabor, Biro Gabor, Kovacs CsabaOP10 ...