BAC-FISH refutes report of an 8p22–8p23.1 inversion or duplication in 8 patients with Kabuki syndrome

BACKGROUND: Kabuki syndrome is a multiple congenital anomaly/mental retardation syndrome. The syndrome is characterized by varying degrees of mental retardation, postnatal growth retardation, distinct facial characteristics resembling the Kabuki actor's make-up, cleft or high-arched palate, brachydactyly, scoliosis, and persistence of finger pads. The multiple organ involvement suggests that this is a contiguous gene syndrome but no chromosomal anomalies have been isolated as an etiology. Recent studies have focused on possible duplications in the 8p22–8p23.1 region but no consensus has been reached. METHODS: We used bacterial artificial chromosome-fluorescent in-situ hybridization (BAC-FISH) and G-band analysis to study eight patients with Kabuki syndrome. RESULTS: Metaphase analysis revealed no deletions or duplications with any of the BAC probes. Interphase studies of the Kabuki patients yielded no evidence of inversions when using three-color FISH across the region. These results agree with other research groups' findings but disagree with the findings of Milunsky and Huang. CONCLUSION: It seems likely that Kabuki syndrome is not a contiguous gene syndrome of the 8p region studied

Duplications and copy number variants of 8p23.1 are cytogenetically indistinguishable but distinct at the molecular level

It has been proposed that duplications of 8p23.1 are either euchromatic variants of the 8p23.1 defensin domain with no phenotypic consequences or true duplications associated with developmental delay and heart defects. Here, we provide evidence for both alternatives in two new families. A duplication of most of band 8p23.1 (circa 5 Mb) was found in a girl of 8 years with pulmonary stenosis and mild language delay. BAC fluorescence in situ hybridisation (FISH) and multiplex amplifiable probe hybridisation (MAPH) showed that the two copies of the duplicated segment were sited, in an alternating fashion, between three copies of a circa 300?450 kb segment from 8p23.1 distal to REPD. Copy number of the variable 8p23.1 defensin domain was consistent with duplication but within the normal range. Duplication of the GATA-binding protein 4 gene (GATA4) in this patient and others with and without heart defects, suggests it is a dosage-sensitive gene with variable penetrance. A cytogenetically similar duplication of 8p23.1 was found at prenatal diagnosis in a fetus, father and grandmother. There was no duplication using BAC FISH but MAPH showed 11 copies of the 360 kb variable defensin domain which is within the expanded range found in previous euchromatic variant carriers. Semiquantitative FISH (SQ-FISH) was consistent with a simultaneous expansion of the adjacent olfactory receptor repeats. These results distinguish duplications of 8p23.1 with clinically significant consequences from benign copy number variants, which have not yet been associated with qualitative or quantitative traits

Nanotechnology in perspective. Risks for man and the environment

Het Kennis- en Informatiepunt Risico's van Nanotechnologie (KIR-nano) van het RIVM heeft de potentiele risico's van blootstelling van gefabriceerde, vrije, onafbreekbare en onoplosbare nanodeeltjes in kaart gebracht. In dit rapport worden de risico's voor de mens als werknemer, patient en consument behandeld, evenals risico's voor het milieu. Drie toepassingsgebieden zijn daarbij relevant: geneesmiddelen en medische technologie, voedselproductie en consumentenproducten. De huidige stand van zaken van de wetenschap laat zien dat risico's niet uit te sluiten zijn. Er ontbreekt echter nog veel kennis om de risico's even goed in te kunnen schatten als voor 'chemische stoffen niet in nanovorm'. Toch zijn er al vele honderden producten waarin nanomaterialen zijn verwerkt op de markt. Dit vereist op korte termijn veel onderzoek naar de blootstelling en toxiciteit van deze materialen. Helaas is het aantal onderzoeksvragen dusdanig groot en fundamenteel van aard dat het nog jaren zal duren voordat alle informatie is vergaard. KIR-nano adviseert daarom het onderzoek vooral te richten op die vragen die cruciale informatie voor de risicobeoordeling voor mens en milieu bieden. Afhankelijk van het perspectief van werknemer, consument, patient of milieu zijn oplossingsrichtingen gedefinieerd voor het beheersen van de risico's. Informatie die in de streng gereguleerde wereld van medische toepassingen wordt gegenereerd kan met name vanuit methodologisch oogpunt zeer waardevol zijn voor andere toepassingsgebieden, waar de dossiervereisten en dus veelal ook de informatievergaring (veel) beperkter voor zijn. Kernbegrippen voor de komende jaren zijn samen te vatten onder KOKOS: Kennis vergroten en uitwisselen om dubbeling van onderzoek te voorkomen, Oplossingsrichtingen en risicomanagement, Keuzes maken in bijdragen vanuit Nederland aan dit onderzoeksveld, Onderzoek & Ontwikkeling, en Samenwerking bevorderen tussen wet- en regelgevende kaders, wetenschap en bedrijfsleven.The Knowledge and Information Risks Nanotechnology (KIR nano), a Dutch national government-supported observation organization based at RIVM, has provided an overview of the potential risks to both man and the environment of exposure to nanoparticles. The focus is on free, non-degradable and insoluble nanoparticles present in medical applications, food, consumer products and the environment. Scientific data compiled to date demonstrate that negative effects of exposure to nanoparticles cannot be excluded. However, much more information is required to be able to estimate the risks of nanoparticles equally well as those of other (not nano) chemicals. Nevertheless, hundreds of products containing nanomaterials are currently available commercially, a situation which clearly necessitates that the exposure and toxicity of these materials be investigated in the near future. Unfortunately, the research questions to be answered are so numerous that it will take years to compile the relevant data. The advice of the KIR nano is to focus research primarily on those questions that provide information critical to the assessment of risks to man and the environment. Dependent on the perspective - worker, consumer, patient, or the environment - the points of departure can then be defined for controlling (or limiting) the risks. Information (eg. on methodology) generated in the strongly regulated world of medical applications can be a very valuable asset in other (research) areas of application, where the requirements for dossiers and compiling of pertinent data are not as exacting. Core concepts for the upcoming years include expanding our knowledge of nanoparticles and making this knowledge easily available to avoid any duplication of research, identifying and where necessary taking the appropriate risk management measures, choosing the areas of research in which the Netherlands wishes to contribute to this field, supporting Research & Development and promoting collaboration between (semi)government organs/agencies, science and industry.VROMVWSSZ