Genome-wide association studies have identified breast cancer risk variants in over 150 genomic regions, but the mechanisms underlying risk remain largely unknown. These regions were explored by combining association analysis with in silico genomic feature annotations. We defined 205 independent risk-associated signals with the set of credible causal variants (CCVs) in each one. In parallel, we used a Bayesian approach (PAINTOR) that combines genetic association, linkage disequilibrium, and enriched genomic features to determine variants with high posterior probabilities of being causal. Potentially causal variants were significantly over-represented in active gene regulatory regions and transcription factor binding sites. We applied our INQUSIT Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Indian hedgehog (IHH) is a secreted signaling molecule of the hedgehog family known to play important roles in the regulation of chondrocyte differentiation, cortical bone formation, and the development of joints. Here, we describe that copy-number variations of the IHH locus involving conserved noncoding elements (CNEs) are associated with syndactyly and craniosynostosis. These CNEs are able to drive reporter gene expression in a pattern highly similar to wild-type Ihh expression. We postulate that the observed duplications lead to a misexpression and/or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development.

Understanding the intermediate- and long-term psychological consequences of genetic testing for cancer patients has led to encouraging research, but a clear consensus of the psychosocial impact and clinical routine for cancer-affected BRCA1 and BRCA2 mutation carriers is still missing. We performed a systematic review of intermediate- and long-term studies investigating the psychological impact like psychological distress, anxiety, and depression in cancer-affected BRCA mutation carriers compared to unaffected mutation carriers. This review included the screening of 1243 studies. Eight intermediate- and long-term studies focusing on distress, anxiety, and depression symptoms among cancer-affected mutation carriers at least six months after the disclosure of genetic testing results were included. Studies reported a great variety of designs, methods, and patient outcomes. We found evidence indicating that cancer-affected mutation carriers experienced a negative effect in relation to psychological well-being in terms of an increase in symptoms of distress, anxiety, and depression in the first months after test disclosure. In the intermediate- and long-term, no significant clinical relevant symptoms occurred. However, none of the included studies used specific measurements, which can clearly identify psychological burdens of cancer-affected mutation carriers. We concluded that current well-implemented distress screening instruments are not sufficient for precisely identifying the psychological burden of genetic testing. Therefore, future studies should implement coping strategies, specific personality structures, the impact of genetic testing, supportive care needs and disease management behaviour to clearly screen for the possible intermediate- and long-term psychological impact of a positive test disclosure.

We could identify novel microimbalances as the probable cause of mental retardation in 10% of patients with unclear etiology. The gene content of the microimbalances was found to correlate with phenotype severity. Precise breakpoint analyses allowed the identification of deleted genes presumably causing mental retardation.

Congenital disorder of glycosylation type Id is an inherited glycosylation disorder based on a defect of the first mannosyltransferase involved in N-glycan biosynthesis inside the endoplasmic reticulum. Only one patient with this disease has been described until now. In this article, a second patient and an affected fetus are described. The patient showed abnormal glycosylation of several plasma proteins as demonstrated by isoelectric focusing and Western blot. Lipid-linked oligosaccharides in the endoplasmic reticulum, reflecting early N-glycan assembly, revealed an accumulation of immature Man 5 GlcNAc 2 -glycans in fibroblasts of the patient. Chorion cells of the affected fetus showed the same characteristic lipid-linked oligosaccharides pattern. However, the fetus had a normal glycosylation of several plasma proteins. Some fetal glycoproteins are known to be derived from the mother, but even glycoproteins that do not cross the placenta were normally glycosylated in the affected fetus. Maternal or placental factors that partially compensate for the glycosylation defect in the fetal stage must be proposed and may be relevant for the therapy of these disorders in the future. Inherited defects that affect the biosynthesis of N-or O-glycans are named congenital disorders of glycosylation (CDG) (1). N-linked glycans are attached to asparagine residues of the protein when the Asn occurs within the consensus sequence Asn-X-Ser/Thr. A precursor glycan (Glc 3 Man 9 GlcNAc 2 ) is first assembled in the endoplasmic reticulum on a lipid (dolichol) anchor via a pyrophosphate linkage (Glc 3 Man 9 GlcNAc 2 -PP-dolichol). The glycan is transferred from the anchor to nascent protein and is processed further in the endoplasmic reticulum and Golgi apparatus. O-glycans are attached to serine or threonine residues of the protein via a GalNAc-␣-Ser/Thr linkage and are elongated one sugar at a time; this process occurs in the endoplasmic reticulum and Golgi apparatus. The biochemical compartmentation of the assembly of N-and O-glycans gave rise to the classification of CDG into two subgroups, type I affecting the assembly of the precursor N-glycans on the lipid anchor in the endoplasmic reticulum and type II affecting the processing of the N-glycan after transfer to the protein (2). In recent years, 17 different CDG were characterized, and recently disorders of N-or O-glycosylation that are not yet part of the CDG nomenclature were described (3-5).In 1995, Stibler et al. (6) described two patients with severe psychomotor retardation and an abnormal isoelectric focusing (IEF) pattern of transferrin, suspecting a new subtype of CDG. The biochemical and molecular defect of one patient could subsequently be elucidated by Körner et al. (7), who found a defect in the assembly of lipid-linked oligosaccharides (LLO) in the endoplasmic reticulum of the patient with an accumulation of Man 5 GlcNAc 2 -PP-dolichol. A missense mutation in the human ALG3 gene (8) (synonym: NOT56L, neighbor of tumorous imaginal discs-like protein) coding for doli...