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Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

Amelogenesis imperfecta (AI) is a clinically and genetically heterogeneous disorder of tooth development which is due to aberrant deposition or composition of enamel. Both syndromic and isolated forms exist; they may be inherited in an X-linked, autosomal recessive, or autosomal dominant manner. WDR72 is one of ten currently known genes for recessive isolated AI; nine WDR72 mutations affecting single nucleotides have been described to date. Based on whole exome sequencing in a large consanguineous AI pedigree, we obtained evidence for presence of a multi-exonic WDR72 deletion. A home-made multiplex ligation-dependent probe amplification assay was used to confirm the aberration, to narrow its extent, and to identify heterozygous carriers. Our study extends the mutational spectrum for WDR72 to include large deletions, and supports a relevance of the previously proposed loss-of-function mechanism. It also introduces an easy-to-use and highly sensitive tool for detecting WDR72 copy number alterations.

J. Hentschel1, M. Jager1, N. Beiersdorf1,2, F. Doht1, R. Michl1, U.R. Markert2, K. Boer3, P. Keller4, M.W. Pletz5, J.G. Mainz1. 1Jena University Hospital, CF-Centre, Paediatrics, Jena, Germany; 2Jena University Hospital, Department of Obstetrics, Placenta Laboratory, Jena, Germany; 3Jena University Hospital, Institute for Clinical Chemistry and Laboratory Diagnostics, Jena, Germany; 4Jena University Hospital, Institute of Medical Microbiology, Jena, Germany; 5Jena University Hospital, Center for Infectious Diseases and Infection Control, Jena, Germany

Objectives Chronic rhinosinusitis significantly impairs CF patients' quality of life. The PariSinus™ device effectively delivers vibrating aerosols to paranasal sinuses. Previously, we demonstrated a significant reduction of sinonasal symptoms by inhalation of dornase alfa with the device (JCF 2014). Bronchially inhaled hypertonic saline (3–7%) was shown to reduce pulmonary symptoms and exacerbations in CF. Aims of this multicentre, double-blind, controlled, crossover trial were to assess effects of hypertonic (6%) and isotonic saline on sinonasal outcome measures. Methods 69 CF patients were randomised to inhale either hypertonic or isotonic saline for 28 days with the PariSinus™. After 28 days of wash-out patients crossed over to the alternative treatment. The primary outcome parameter was upper airway symptoms / disease-specific QoL (Sino-Nasal Outcome Test-20 – SNOT-20). Results Sinonasal inhalation of isotonic and hypertonic saline was well tolerated. Both arms showed slight but not significant reductions of SNOT-20 scores (6% –3.1±6.5pts/0.9% –5.1±8.3pts). Interestingly, a post-hoc analysis of the single therapeutic periods revealed a significant improvement, especially for isotonic saline. We additionally present changes in rhinoscopy, rhinomanometry, and cytokines in nasal lavage. Conclusion Compared to sinonasal inhalation with dornase alfa, effects of isotonic and hypertonic saline on sinonasal symptoms did not reach significance. Possibly, SNOT-20 is not the best outcome parameter for therapy with hypertonic saline due to irritating properties, even if patients reported effective mobilization of mucus, which is difficult to quantify in both airway levels.

Objectives Upper airway (UAW) infections are common in CF patients with nasal congestion, impaired climate function and reduced quality of life. Moreover, by postnasal drip, infections can descend to the lungs. Actually, there are no data comparing UAW infection and inflammation in CF and healthy controls in stable phases and during exacerbation. Methods We collected epithelial lining fluid from 49 CF patients and 38 healthy controls by nasal lavage in stable phases and during UAW infection. Microbiological (only CF cohort), cytological and immunological analyses (NE/IL-6/IL-8/IL-1β/MMP-9/TIMP-1) were performed. Results During UAW infection all measured inflammatory mediators increased in both, CF patients and the control cohort. Whereas levels of IL-6 and IL-8 were significantly higher in CF under stable conditions compared to healthy controls, the levels of the control cohort exceeded those of CF patients during infection. Age-stratified analyses showed higher releases of mediators during acute UAW infection in CF patients ≤12 years, especially for MMP-9, IL-8 and TIMP-1. These findings were not present in controls. Conclusion In CF patients, chronic inflammation with higher values of inflammatory mediators compared to healthy controls was observed. However, the increase of inflammation during UAW infection is not higher in CF compared to healthy controls. In contrast, for all measured parameters except TIMP-1 a weaker increase was observed in CF, suggesting a deregulation of the immune system in CF with a decreased ability of mediator release. This hypothesis is also supported by the observation of higher releases of MMP-9, TIMP-1 and IL-8 in younger CF patients.