Molecular diagnostics of rare inherited SYNDROMES with a view on diagnostic test development

CHARGE syndrome, Sotos syndrome and 3p deletion syndrome are examples of rare inherited syndromes that have been recognized for decades but for which the molecular diagnostics only have been made possible by recent advances in genomic research. Despite these advances, development of diagnostic tests for rare syndromes has been hindered by diagnostic laboratories having limited funds for test development, and their prioritization of tests for which a (relatively) high demand can be expected. In this study, the molecular diagnostic tests for CHARGE syndrome and Sotos syndrome were developed, resulting in their successful translation into routine diagnostic testing in the laboratory of Medical Genetics (UTUlab). In the CHARGE syndrome group, mutation was identified in 40.5% of the patients and in the Sotos syndrome group, in 34%, reflecting the use of the tests in routine diagnostics in differential diagnostics. In CHARGE syndrome, the low prevalence of structural aberrations was also confirmed. In 3p deletion syndrome, it was shown that small terminal deletions are not causative for the syndrome, and that testing with arraybased analysis provides a reliable estimate of the deletion size but benign copy number variants complicate result interpretation. During the development of the tests, it was discovered that finding an optimal molecular diagnostic strategy for a given syndrome is always a compromise between the sensitivity, specificity and feasibility of applying a new method. In addition, the clinical utility of the test should be considered prior to test development: sometimes a test performing well in a laboratory has limited utility for the patient, whereas a test performing poorly in the laboratory may have a great impact on the patient and their family. At present, the development of next generation sequencing methods is changing the concept of molecular diagnostics of rare diseases from single tests towards whole-genome analysis.

Hevosen herpesvirus 1 (EHV-1) : neljän syndrooman virus : tapausselostus ja kirjallisuuskatsaus

Summary: Equine herpesvirus 1 (EHV-1) - the virus with four syndromes : a case report and a review of literature

Filmipäällystimen nippitapahtuman vaikutus päällystyskoneen ajettavuuteen

Työn tavoitteena oli syventyä filmipäällystimen nippitapahtumaan ja siellä tapahtuviin ilmiöihin. Tämän lisäksi selvitettiin esipäällystysparametrien ja pohjapaperin merkitys filmipäällystimen ajettavuudelle. Erityisesti pyrittiin selvittämään päällystemäärän ja applikointitelojen momenttieron vaikutus ajettavuuteen sekä kiihdytysvaiheessa ilmenevien ajettavuusongelmien syntymekanismit. Työn kokeellinen osa jakaantui kahteen osaan. Ensimmäisessä osassa pyritään löytämään lisäymmärrystä nippitapahtuman ilmiöille joita sitten hyödynnetään toisen osan koeajoissa. Staattisilla kuormituskokeilla tutkittiin telapinnan kokoonpuristumista ja suurnopeus-kamerakuvauksilla nipin geometriaa päällystyskoneen ajon aikana. Applikointitelojen momenttierokoeajoilla pyrittiin selvittämään paperiradan mahdollista luistoa nipissä. MCA-kosteuspitoisuusanalysaattorilla mitattiin nippitapahtuman muutosten vaikutusta filmipäällystimen paluufilmin ominaisuuksiin. Muuttelemalla päällystemäärää ja – jakaumaa sekä applikointitelojen momenttieroa selvitettiin esipäällystysparametrien vaikutus filmipäällystimen ajettavuuteen. Muokkaamalla pohjapaperin absorptiokykyä sekä pastan vedenpidätyskykyä tutkittiin nestepenetraation vaikutusta ajettavuuteen. Telapinnan kokoonpuristuman havaittiin olevan pieni eikä ajon aikana nipin geometriassa havaittu muutoksia. Paperiradan todettiin luistavan nipissä, mutta luistoilmiö oli huomattavasti pienempi mitä nopeuserolukemista voidaan päätellä. Kiihdytysvaiheessa havaittiin selviä muutoksia paluufilmissä, mutta ajon aikana paluufilmi pysyi lähes vakiona. Päällystemäärän todettiin olevan suurin yksittäinen tekijä filmipäällystimen ajettavuudessa ja siihen tulee kiinnittää erityistä huomiota filmipäällystimen kiihdytysvaiheessa. Aukirullauksen levitystelan vaihdon myötä todettiin pohjapaperiin kohdistuvilla kuormituksilla olevan myös suuri merkitys filmipäällystimen ajettavuudelle.

Objective Evaluation of Nasal Dimensions in Children with Acoustic Rhinometry

Aims: This study was carried out to investigate the usefulness of acoustic rhinometry in the evaluation of intranasal dimensions in children. The aim was to define reference values for school children. In addition, the role of the VAS scale in the subjective evaluation of nasal obstruction in children was studied. Materials and methods: Measurements were done with Acoustic Rhinometry A1. The values of special interest were the minimal cross-sectional area (MCA) and the anterior volume of the nose (VOL). The data for reference values included 124 voluntary school children with no permanent nasal symptoms, aged between 7 and 14 years. Data were collected at baseline and after decongestion of the nose; the VAS scale was filled in before measurements. The subjects in the follow-up study (n=74, age between 1 and 12 years) were receiving intranasal spray of insulin or placebo. The nasal symptoms were recorded and acoustic rhinometry was measured at each control visit. Results: In school children, the mean total MCA was 0.752 cm2 (SD 0.165), and the mean total VOL was 4.00 cm3 (SD 0.63) at baseline. After decongestion, a significant increase in the mean TMCA and in the mean TVOL was found. A correlation was found between TMCA and age, and between TVOL and height of a child. There was no difference between boys and girls. A correlation was found between unilateral acoustic values and VAS at baseline, but not after decongestion. No difference wasfound in acoustic values or symptoms between the insulin and placebo group in the follow-up study of two years. Conclusions: Acoustic rhinometry is a suitable objective method to examine intranasal dimensions in children. It is easy to perform and well tolerated. Reference values for children between 7 and 14 years were established.