Mapping complex and monogenetic disorders:methods and applications

Steeds meer kennis komt beschikbaar over de invloed van onze genetische kenmerken op het ontstaan van ziekten. Sommige ziekten worden veroorzaakt door één enkel gen (monogene ziekten), andere door een veelheid aan genen. Bij veel ziekten spelen naast genetische eigenschappen ook omgevingsfactoren een rol. Agata Szperl onderzocht welke mogelijkheden nieuwe genetische analysetechnieken bieden bij het ontrafelen van de oorzaken van ziekten. In haar proefschrift presenteert Szperl een breed scala aan technieken die vaak gebruikt worden in het huidige medisch genetisch onderzoek naar genen en mutaties die betrokken zijn bij het ontstaan van verschillende ziekten. Ze bestudeert zowel monogene als complexe ziekten, waarbij zij zich baseert op genetisch materiaal van zowel afzonderlijke families als de algemene bevolking. Door het gebruik van de positionele-kandidaat gen methode, etnische fine-mapping en genoomwijde sequencing identificeerde Szperl de genetische mutaties die ten grondslag liggen aan een aantal ziekten, of wist zij de chromosomale regio waarin het verantwoordelijke gen ligt te versmallen. Szperl gaat uitvoerig in op “next generation sequencing”, een nieuwe techniek die kan worden gebruikt om de meeste monogene en sommige complexe aandoeningen nu en in de toekomst te verklaren

Expression of cellular retinoic acid-binding protein I and II (CRABP I and II) in embryonic mouse hearts treated with retinoic acid

Cellular retinoic acid binding proteins are considered to be involved in retinoic acid (RA) signaling pathways. Our aim was to compare the expression and localization of cellular retinoic acid binding proteins I and II (CRABP I and II) in embryonic mouse hearts during normal development and after a single teratogenic dose of RA. Techniques such as real-time PCR, RT-PCR, Western blots and immunostaining were employed to examine hearts from embryos at 9-17 dpc. RA treatment at 8.5dpc affects production of CRABP I and II in the heart in the 48-h period. Changes in expression of mRNA for retinaldehyde dehydrogenase II (Raldh2), Crabp1 and Crabp2 genes also occur within the same time window (i.e. 10-11dpc) after RA treatment. In the embryonic control heart these proteins are localized in groups of cells within the outflow tract (OT), and the atrioventricular endocardial cushions. A gradient of labeling is observed with CRABP II but not for CRABP I along the myocardium of the looped heart at 11 dpc; this gradient is abolished in hearts treated with RA, whereas an increase of RALDH2 staining has been observed at 10 dpc in RA-treated hearts. Some populations of endocardial endothelial cells were intensively stained with anti-CRABP II whereas CRABP I was negative in these structures. These results suggest that CRABP I and II are independently regulated during heart development, playing different roles in RA signaling, essential for early remodeling of the heart tube and alignment of the great arteries to their respective ventricles

QTc prolongation in patients with hearing loss: Electrocardiographic and genetic study

Background: The aim of the study was to determine, whether electrocardiogram (ECG) screening could reduce the risk of sudden cardiac death in patients with hearing loss through the early diagnosis of Jervell and Lange-Nielsen syndrome and the introduction of the therapy. Methods: One thousand and eighty patients with hearing loss (aged 21.8 ± 19.9 years) underwent ECG. Additionally, all subjects were asked to complete a 3-question survey. Those who met, at least, one of the high-risk criteria underwent further cardiac assessment and genetic testing. Results: QTc assessment was possible in 1,027 patients. Mean QTc measured 422.8 ± 23.7 ms in 313 women, 414.9 ± 27.7 ms in 273 men and 421.1 ± 21.5 ms in 441 children (individuals younger than 14 years). Abnormal QTc was found in 13 (4.1%) women, 20 (7.3%) men, and 72 (16.3%) children. In the studied group, no recessive mutation of KNCQ1 or KCNE1 was found. In 6 patients, other mutations were found: in KCNQ1 (n = 1), in KCNH2 (n = 3) and in SCN5A (n = 1), which were pathogenic for long-QT-syndromes (LQTS), and 2 mutations of unknown clinical significance in SCN5A. Overall, out of these 6 patients LQTS was diagnosed in 3 asymptomatic patients, but with abnormal QTc and in 2 patients with normal QTc, but who were previously treated for epilepsy. Conclusions: Jervell and Lange-Nielsen syndrome is a very rare condition even in a population with hearing loss. In this population, the prevalence of prolonged QT interval is increased over the general population. Further investigations are necessary.

Fine mapping of the celiac disease-associated LPP locus reveals a potential functional variant

Transplantation and immunomodulatio

Next-generation sequencing for diagnosis of thoracic aortic aneurysms and dissections: diagnostic yield, novel mutations and genotype phenotype correlations

Additional file 1. Complementary data on primer sequences, SKI amplification and survival analyses