Center for Human Genetics

Vienna, Austria

Center for Human Genetics

Vienna, Austria
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Milunsky A.,Center for Human Genetics | Milunsky A.,Tufts University
Journal of the American Board of Family Medicine | Year: 2017

Major advances in human genetics have led to the identification of 4451 genes to date with disease-carrying mutations, thereby enabling precise diagnoses of all of these monogenic disorders. Limitations to the use of the "new genetics" do exist, however, including the recognition of genetic heterogeneity, many variants of unknown significance, and incidental diagnoses. This article reviews information to help use these advances to aid accurate diagnoses, identify carriers, and determine prenatal diagnoses, providing opportunities to avoid or prevent serious and fatal genetic disorders.

McPherson E.,Center for Human Genetics
American Journal of Medical Genetics, Part A | Year: 2016

In 1964, the landmark paper of Marden, Smith, and McDonald established that multiple minor anomalies in newborn infants are associated with an increased risk for major malformations. There were until now no comparable studies in stillbirths. The Wisconsin Stillbirth Service Program (WiSSP) has data regarding nearly 3,000 stillbirths and second trimester losses that have been analyzed for major anomalies and cause of death. One dysmorphologist retrospectively reviewed all 2,397 with usable photographs. Minor anomalies were identified in 1,413 (59%) with 575 of these (41%) having at least one major anomaly. Probability of a major anomaly increased from 7% with no minor anomalies to 15%, 36%, 67%, and 89% with 1, 2, 3, and >33 minor anomalies, respectively. Frequency of minor anomalies was less with lower resolution photographs, but did not show significant differences with maceration or gestational age. The most frequent minor anomalies were infraorbital creases/folds, lowset/posteriorly angulated ears, nuchal edema, flat face, equinovarus foot, camptodactyly, upslanted palpebral fissures, ear antihelix abnormalities (combined), micrognathia/retrognathia, and single transverse palmar crease. Except for infraorbital creases/folds each of these minor anomalies was strongly correlated with major anomalies (P<0.0001). Infraorbital folds were the only anomaly which increased with placental cause of death, and reanalysis with placental causes excluded showed the expected relationship to major anomalies, suggesting that infraorbital folds may be markers for oligohydramnios due to various causes including placental hypoperfusion. Minor anomalies correlate with presence of major anomalies in stillborn fetuses, regardless of gestational age and maceration, and can provide information to guide decisions regarding laboratory testing and other evaluations. © 2015 Wiley Periodicals, Inc.

Bergmann C.,Center for Human Genetics | Bergmann C.,University Hospital Freiburg
Pediatric Nephrology | Year: 2015

Renal cysts are clinically and genetically heterogeneous conditions. Polycystic kidney disease (PKD) is common and its characterization has paved the way for the identification of a growing number of cilia-related disorders (ciliopathies) of which most show cystic kidneys. While the recessive form of PKD (ARPKD) virtually always presents in childhood, early onset can, in some instances, also occur in the dominant form (ADPKD). Both ADPKD genes (PKD1 and PKD2) can also be inherited in a recessive way, making the story more complex with evidence for a dosage-sensitive network. Several phenocopies are known, and mutations in HNF1ß or genes that typically cause other ciliopathies, such as nephronophthisis, Bardet–Biedl, Joubert syndrome and related disorders, can mimic PKD. An accurate genetic diagnosis is crucial for genetic counseling, prenatal diagnostics, and the clinical management of patients and their families. The increasing number of genes that have to be considered in patients with cystic kidney disease is challenging to address by conventional techniques and largely benefits from next-generation sequencing-based approaches. The parallel analysis of targeted genes considerably increases the detection rate, allows for better interpretation of identified variants, and avoids genetic misdiagnoses. © 2014, The Author(s).

De Strooper B.,Center for Human Genetics | Vassar R.,Northwestern University | Golde T.,Mayo Medical School
Nature Reviews Neurology | Year: 2010

The amyloid hypothesis has yielded a series of well-validated candidate drug targets with potential for the treatment of Alzheimer disease (AD). Three proteases that are involved in the processing of amyloid precursor proteinα-secretase, Β-secretase and γ-secretaseare of particular interest as they are central to the generation and modulation of amyloid-Β peptide and can be targeted by small compounds in vitro and in vivo. Given that these proteases also fulfill other important biological roles, inhibiting their activity will clearly be inherently associated with mechanism-based toxicity. Carefully determining a suitable therapeutic window and optimizing the selectivity of the drug treatments towards amyloid precursor protein processing might be ways of overcoming this potential complication. Secretase inhibitors are likely to be the first small-molecule therapies aimed at AD modification that will be fully tested in the clinic. Success or failure of these first-generation AD therapies will have enormous consequences for further drug development efforts for AD and possibly other neurodegenerative conditions. © 2010 Macmillan Publishers Limited. All rights reserved.

De Strooper B.,Center for Human Genetics
Physiological Reviews | Year: 2010

Alzheimer disease is characterized by the accumulation of abnormally folded protein fragments, i.e., amyloid beta peptide (Aβ) and tau that precipitate in amyloid plaques and neuronal tangles, respectively. In this review we discuss the complicated proteolytic pathways that are responsible for the generation and clearance of these fragments, and how disturbances in these pathways interact and provide a background for a novel understanding of Alzheimer disease as a multifactorial disorder. Recent insights evolve from the static view that the morphologically defined plaques and tangles are disease driving towards a more dynamic, biochemical view in which the intermediary soluble Aβ oligomers and soluble tau fragments are considered as the main mediators of neurotoxicity. The relevance of proteolytic pathways, centered on the generation and clearance of toxic Aβ, on the cleavage and nucleation of tau, and on the general proteostasis of the neurons, then becomes obvious. Blocking or stimulating these pathways provide, or have the potential to provide, interesting drug targets, which raises the hope that we will be able to provide a cure for this dreadful disorder. Copyright © 2010 the American Physiological Society.

Bergmann C.,Center for Human Genetics | Bergmann C.,RWTH Aachen | Weiskirchen R.,RWTH Aachen
Journal of Hepatology | Year: 2012

Autosomal dominant polycystic liver disease results from mutations in PRKCSH or SEC63. The respective gene products, glucosidase IIβ and SEC63p, function in protein translocation and quality control pathways in the endoplasmic reticulum. Here we show that glucosidase IIβ and Sec63p are required in mice for adequate expression of a functional complex of the polycystic kidney disease gene products, polycystin-1 and polycystin-2. We find that polycystin-1 is the rate-limiting component of this complex and that there is a dose-response relationship between cystic dilation and levels of functional polycystin-1 following mutation of Prkcsh or Sec63. Reduced expression of polycystin-1 also serves to sensitize the kidney to cyst formation resulting from mutations in Pkhd1, the recessive polycystic kidney disease gene. Finally, we show that proteasome inhibition increases steady-state levels of polycystin-1 in cells lacking glucosidase IIβ and that treatment with a proteasome inhibitor reduces cystic disease in orthologous gene models of human autosomal dominant polycystic liver. © 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.

Uytterhoeven V.,Laboratory of Neuronal Communication | Uytterhoeven V.,Center for Human Genetics | Kuenen S.,Laboratory of Neuronal Communication | Kuenen S.,Center for Human Genetics | And 6 more authors.
Cell | Year: 2011

Exchange of proteins at sorting endosomes is not only critical to numerous signaling pathways but also to receptor-mediated signaling and to pathogen entry into cells; however, how this process is regulated in synaptic vesicle cycling remains unexplored. In this work, we present evidence that loss of function of a single neuronally expressed GTPase activating protein (GAP), Skywalker (Sky) facilitates endosomal trafficking of synaptic vesicles at Drosophila neuromuscular junction boutons, chiefly by controlling Rab35 GTPase activity. Analyses of genetic interactions with the ESCRT machinery as well as chimeric ubiquitinated synaptic vesicle proteins indicate that endosomal trafficking facilitates the replacement of dysfunctional synaptic vesicle components. Consequently, sky mutants harbor a larger readily releasable pool of synaptic vesicles and show a dramatic increase in basal neurotransmitter release. Thus, the trafficking of vesicles via endosomes uncovered using sky mutants provides an elegant mechanism by which neurons may regulate synaptic vesicle rejuvenation and neurotransmitter release. © 2011 Elsevier Inc.

Cox L.,Center for Human Genetics | Cools J.,Center for Human Genetics
Chemistry and Biology | Year: 2011

Janus kinases are important signaling proteins implicated in cytokine signaling. In particular, Janus kinase 3 (JAK3) has gained attention as a target for inhibition of the immune system, due to its importance for T and B cell development and function. In this issue however, Haan et al. (2011) show that inhibition of JAK3 activity may not be sufficient for this purpose. © 2011 Elsevier Ltd.

Biancalana V.,University of Monastir | Glaeser D.,Center for Human Genetics | McQuaid S.,Our Ladys Childrens Hospital | Steinbach P.,University of Ulm
European Journal of Human Genetics | Year: 2015

Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed 'full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term 'abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the 'normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed 'premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing. © 2015 Macmillan Publishers Limited All rights reserved.

Hebbring S.J.,Center for Human Genetics
Immunology | Year: 2014

Over the last decade, significant technological breakthroughs have revolutionized human genomic research in the form of genome-wide association studies (GWASs). GWASs have identified thousands of statistically significant genetic variants associated with hundreds of human conditions including many with immunological aetiologies (e.g. multiple sclerosis, ankylosing spondylitis and rheumatoid arthritis). Unfortunately, most GWASs fail to identify clinically significant associations. Identifying biologically significant variants by GWAS also presents a challenge. The GWAS is a phenotype-to-genotype approach. As a complementary/alternative approach to the GWAS, investigators have begun to exploit extensive electronic medical record systems to conduct a genotype-to-phenotype approach when studying human disease - specifically, the phenome-wide association study (PheWAS). Although the PheWAS approach is in its infancy, this method has already demonstrated its capacity to rediscover important genetic associations related to immunological diseases/conditions. Furthermore, PheWAS has the advantage of identifying genetic variants with pleiotropic properties. This is particularly relevant for HLA variants. For example, PheWAS results have demonstrated that the HLA-DRB1 variant associated with multiple sclerosis may also be associated with erythematous conditions including rosacea. Likewise, PheWAS has demonstrated that the HLA-B genotype is not only associated with spondylopathies, uveitis, and variability in platelet count, but may also play an important role in other conditions, such as mastoiditis. This review will discuss and compare general PheWAS methodologies, describe both the challenges and advantages of the PheWAS, and provide insight into the potential directions in which PheWAS may lead. © 2013 The Authors. Immunology Published by John Wiley & Sons Ltd.

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