Genetic association signal near NTN4 in Tourette syndrome.

Tourette syndrome (TS) is a neurodevelopmental disorder with a complex genetic etiology. Through an international collaboration, we genotyped 42 single nucleotide polymorphisms (p < 10(-3) ) from the recent TS genomewide association study (GWAS) in 609 independent cases and 610 ancestry-matched controls. Only rs2060546 on chromosome 12q22 (p = 3.3 × 10(-4) ) remained significant after Bonferroni correction. Meta-analysis with the original GWAS yielded the strongest association to date (p = 5.8 × 10(-7) ). Although its functional significance is unclear, rs2060546 lies closest to NTN4, an axon guidance molecule expressed in developing striatum. Risk score analysis significantly predicted case-control status (p = 0.042), suggesting that many of these variants are true TS risk alleles.

Variants in TSPYL1 are not associated with sudden infant death syndrome in a cohort of deceased infants from Switzerland.

Sudden infant death syndrome (SIDS) is currently the major cause of an unexpected and unexplained death of infants in the first year of lifetime in industrialized countries. Besides environmental factors also genetic factors have been identified as risk factors for SIDS. Notably, the mutation c.457dupG (p.Glu153Glyfs*17) in the TSPYL1 gene has been reported to cause autosomal recessive sudden infant death with dysgenesis of the testes syndrome (SIDDT) in an Old Order Amish community in Pennsylvania. The purpose of this study was to analyze whether variants of TSPYL1 are associated with the sudden infant death syndrome (SIDS) in the area of Europe from which the Amish descended. Mutation analysis of the entire TSPYL1 gene was performed in a cohort of 165 SIDS cases with mostly Swiss ethnic origin, in comparison to 163 German controls. Eight known polymorphisms were detected, none of which was significantly associated with SIDS. One deceased girl was heterozygous for the hitherto unreported TSPYL1 variant c.106C>G (p.Leu36Val), and two affected girls were heterozygous for the rare known TSPYL1 variant rs140756663 (c.1098C>A, p.Phe366Leu). In addition, one deceased boy was heterozygous for the rare common silent nucleotide substitution c.718C>T (p.Leu240Leu, rs150144081), while one control was heterozygous for the rare silent nucleotide substitution rs56190632 (c.760C>T; p.Leu254Leu). In silico analyses predicted a likely non-pathogenic effect for p.Leu36Val and p.Phe366Leu, respectively, although protein features might be affected. The Amish founder mutation was not detected in the analyzed SIDS cases and controls. Mutations and polymorphisms in the TSPYL1 gene were not associated with SIDS in a cohort of 165 deceased Swiss infants.

Association of TNF-α polymorphism rs1800629 with multisomatoform disorder in a group of German patients and healthy controls: an explorative study.

INTRODUCTION: The etiology of multisomatoform disorder (MSD) is still largely unknown, but genetic factors seem to have an influence on pathogenesis. Pain is a major symptom of MSD and polymorphisms of different proinflammatory cytokines have been found associated with pain in former studies. Therefore, we presumed that cytokine polymorphisms could also be associated with MSD. PATIENTS AND METHODS: Groups of 148 MSD patients with pain as the leading clinical symptom and 149 age and gender matched healthy controls participated in this study. Nine cytokine polymorphisms were genotyped and statistically analyzed for associations with MSD. RESULTS: Allelic and genotypic associations were found for rs16944 (interleukin 1ß), rs1800629 (tumor necrosis factor) and rs909253 (lymphotoxin α). After correcting for multiple testing, the association of rs1800629 with MSD remained significant. The rare A-allele was correlated with MSD (p=0.007). DISCUSSION: Since the common G-allele of rs1800629 (TNFα) occurs much more often in the control group than in the MSD group it is assumed to be protective. Being carrier of the A-allele seems to be a risk factor for MSD.

1,25-Dihydroxyvitamin D decreases HTRA1 promoter activity in the rhesus monkey--a plausible explanation for the influence of vitamin D on age-related macular degeneration?

Age-related macular degeneration is the major cause of blindness in the elderly worldwide and the risk is influenced by both environmental and genetic risk factors. One important disease-associated region in humans is located on 10q26 and includes the two candidate genes ARMS2 and HTRA1. However, determination of the causative gene has not yet been possible and examining the situation in the rhesus monkey may help understand the situation in humans. In a recent paper, we characterized the rhesus monkey 10q26-orthologue region on chromosome 9 in detail and identified the drusen-associated HTRA1 promoter SNP rs196357513 as a putative risk factor. In this study, we predicted 9 binding sites for the vitamin D-dependent transcription factor vitamin D receptor in the rhesus HTRA1 promoter, one of which is destroyed by the rs196357513-risk allele. As patients with vitamin D deficit are at increased risk for age-related macular degeneration, a luciferase assay in transiently transfected ARPE19-cells was performed to evaluate the influence of the SNP rs196357513 and of 1,25-dihydroxyvitamin D on the rhesus monkey HTRA1 promoter activity. This revealed that the luciferase activity of the promoter construct containing the rs196357513 wild type allele was significantly reduced after vitamin D stimulation. An in silico analysis and literature search imply that this regulation could also play a role in human HTRA1 expression. Moreover, HTRA1 promoter activity of the construct containing the rs196357513 risk allele appeared diminished in comparison to the construct with the wild type allele, albeit this difference was not significant. The lower promoter activity due to the rhesus monkey rs196357513 risk allele apparently contradicts the common hypothesis for the human HTRA1 promoter risk allele of SNP rs11200638, for which a higher promoter activity has been observed. Our data point to a yet unexpected effect of decreased HTRA1 expression on drusen pathogenesis. Thus not only a higher HTRA1 expression, but an imbalance of HTRA1 might be disease-relevant. Both findings require closer analysis, but if relevance for humans proves true, it would impact current age-related macular degeneration research and treatment.

High-density oligonucleotide-based resequencing assay for mutations causing syndromic and non-syndromic forms of thoracic aortic aneurysms and dissections.

Thoracic aortic aneurysm and dissection is associated with increasing mortality rate that may occur as part of a syndrome or as an isolated familial condition. Several genes have been implicated in causing TAAD, though an appropriate genetic test for their parallel testing is not yet available. Herein, we describe the novel 117-kb "MFSTAAD chip" that may help to understand the genetic basis of TAAD. A custom duplicate resequencing assay was developed to cover eight genes previously described in TAAD; FBN1, TGFBR1&2, COL3A1, MYH11, ACTA2, SLC2A10 and NOTCH1. GSEQ and SeqC software were used for data analysis. The analytical sensitivity of the assay was validated by the recognition of 182 known mutations (153 point mutations, 21 deletions, 7 insertions and 1 duplication) and a cohort of 28 patients were selected to determine the mutation yield, whereby 18 of them were previously negative for mutations in the genes FBN1 and TGFBR2. The assay had significantly higher sensitivity for point mutations (100%) and the largest deletion of 16 bp was detectable through a decline in the hybridization strength. The overall analytical sensitivity was 85%. Mutation testing of 28 unrelated TAAD patients revealed 4 known and 6 possibly pathogenic mutations with a mutation yield of 32%. The MFSTAAD chip is an alternative tool to next-generation sequencing that allows parallel analysis of several genes on a single platform. Refinements in the probe design and data analysis software will increase the analytical sensitivity of insertions and deletions making this assay even more applicable for clinical testing.

Characterization of the 10q26-orthologue in rhesus monkeys corroborates a functional connection between ARMS2 and HTRA1.

Age-related macular degeneration, which is the leading cause of blindness in industrialized countries, is a multifactorial, degenerative disorder of the macula with strong heritability. For age-related macular degeneration in humans, the genes ARMS2 and HTRA1 in the region 10q26 are both promising candidates for being involved in pathogenesis. However, the associated variants are located in a region of strong linkage disequilibrium and so far, the identification of the causative gene in humans was not yet possible. This dilemma might be solved using an appropriate model organism. Rhesus monkeys suffer from drusen, a major hallmark of age-related macular degeneration, and the drusen-phenotype shares susceptibility factors with human macular degeneration. Thus, the rhesus monkey represents a natural animal model to uncover genetic factors leading to macular degeneration. Moreover, the existence of genetically homogenous cohorts offers an excellent opportunity to determine risk factors. However, the 10q26-orthologue genomic region in rhesus monkeys is not characterized in detail so far. Therefore, the aim of this study is to analyze the rhesus linkage disequilibrium structure and to investigate whether variants in ARMS2 or HTRA1 are associated with the drusen-phenotype as well. We sequenced parts of a 20 kb region around ARMS2 and HTRA1 in a genetically homogeneous cohort of 91 rhesus monkeys descending from the CPRC rhesus cohort on Cayo Santiago and currently housed in the German Primate Centre in Göttingen. Within this group, ophthalmoscopic examinations revealed a naturally high drusen prevalence of about 47% in monkeys >5 years. We detected 56 genetic variants within and around ARMS2 and HTRA1 and, as one deviates from Hardy-Weinberg-Equilibrium, 55 polymorphisms were used to generate a linkage disequilibrium-Plot and to perform association studies. We observed strong linkage disequilibrium between the markers and were able to define two haplotype blocks. One of these blocks spanned the whole ARMS2 locus and the 5' part of HTRA1 - almost perfectly resembling the situation found in humans. Tests for association revealed a variant in the promoter region of HTRA1 and two variants in the 5'-UTR of ARMS2 to be associated with drusen. The strong linkage disequilibrium inhibits - as in humans - a determination of the risk gene using statistical methods only. However, the conserved linkage disequilibrium structure in humans and macaques goes in line with the recently emerged dual causality model proposing that ARMS2 and HTRA1 are functionally connected and that both genes contribute to the disease pathology. Moreover, the characterization of the 10q26-orthologue genomic region of the rhesus monkey provides a basis for now needed functional investigations in a well-characterized model organism.

A novel GJC2 mutation associated with hypomyelination and Müllerian agenesis syndrome: coincidence or a new entity?

In recent years, several new white matter diseases have been identified based on magnetic resonance imaging and clinical findings. For most newly defined disorders the genetic basis has been identified. However, there is still a large group of patients without a specific diagnosis. Hypomyelinating leukodystrophies are the largest group among them. In some disorders characterized by hypomyelination only central nervous system involvement is observed, but in some disorders involvement of other organs is observed as well, such as eyes or teeth. Pelizaeus-Merzbacher-like disease (PMLD) is an autosomal recessive hypomyelinating disorder of the central nervous system characterized by nystagmus, ataxia, and progressive spasticity. The disease is caused by mutations in GJC2, the gene that encodes the gap junction protein connexin 47. Here we describe hypomyelination and Müllerian agenesis syndrome in a girl who is homozygous for a novel mutation in the GJC2 gene. It is an open question whether this is an association by chance or a feature of PMLD not previously noted.

Diagnosis of hereditary hemochromatosis in the era of genetic testing.

BACKGROUND: Homozygous C282Y mutation in HFE gene is responsible for the majority of hereditary hemochromatosis cases. Since 1996 this mutation can be identified by a simple genetic test. AIMS: To determine the clinical presentations in patients with homozygous HFE C282Y mutation and the impact of genetic testing on the time needed for diagnosis. METHODS: A total of 414 patients diagnosed with C282Y homozygous hereditary hemochromatosis before and after the introduction of genetic testing were evaluated regarding symptoms and clinical findings at diagnosis as well as first hemochromatosis-related clinical features in their past medical history. RESULTS: At the time of diagnosis, the predominant symptom was joint pain, in particular of the hands/wrists. Those patients presenting with hand/wrist arthralgia had significantly higher ferritin levels than patients without this joint involvement (p = 0.0005 for males and p < 0.0001 for females). After the introduction of the HFE genetic test an earlier diagnosis after first onset of hemochromatosis-associated clinical features was observed between 2006 and 2009 vs. 2000-2005 p = 0.01). CONCLUSIONS: Arthralgia, in particular of the hands/wrists, is a hallmark of hereditary hemochromatosis and its presence is associated with higher ferritin levels. Despite the availability of a genetic test, it often takes more than 6 years from the first onset of clinical features to diagnose hereditary hemochromatosis. This underlines the importance of raising the awareness of hemochromatosis and its typical clinical presentations.

Homozygous CFTR mutation M348K in a boy with respiratory symptoms and failure to thrive. Disease-causing mutation or benign alteration?

UNLABELLED: We report on a 6-month-old premature boy from consanguineous parents. He presented with respiratory distress, necrotizing enterocolitis and hyperbilirubinemia shortly after birth. Persisting respiratory symptoms and failure to thrive prompted cystic fibrosis diagnostics, which showed the lack of wild-type signal for the mutation R347P suggesting a homozygous deletion or an alteration different from the known mutation at this position. Sequencing of this region revealed the homozygous substitution 1175 T > A (HGVS: c.1043 T > A) in exon 7 resulting in the homozygous amino acid change M348K. This mutation has never been reported in homozygosity before. Computational analysis tools classified M348K as 'presumably disease causing.' In our patient, sweat testing and electrophysiological assessment of CFTR function in native rectal epithelium demonstrated normal Cl(-) secretion. CONCLUSION: We assume that the homozygous alteration M348K is a harmless variant rather than a CF-causing mutation.

Mutation nomenclature in practice: findings and recommendations from the cystic fibrosis external quality assessment scheme.

Currently, two nomenclature systems are in use to describe sequence variants for cystic fibrosis: the established traditional nomenclature system and the more recent Human Genome Variation Society (HGVS) nomenclature system. We have evaluated the use of both systems in the laboratory reports of 217 participants in the cystic fibrosis external quality assessment scheme of 2009. The mutation c.1521_1523delCTT (p.Phe508del, F508del) was described by traditional and HGVS nomenclature by 32 of 216 (15%) laboratories that correctly identified the mutation, whereas 171 (79%) laboratories used traditional nomenclature only and 13 (6%) laboratories used HGVS nomenclature only. Overall, 29 of 631 (5%) reports used nomenclature that was evaluated as being seriously incorrect and/or misleading and 136 (22%) reports contained attempts at HGVS coding, of which 104 (76%) contained no coding errors; just 33 (24%) mentioned the correct cDNA name and cited the nucleotide reference sequence. We recognized an urgent need for more consistent and correct usage of nomenclature. We recommended that cystic fibrosis transmembrane conductance regulator testing reports should include a description of the identified sequence variants in both HGVS and traditional nomenclature and provided basic recommendations and other guidance.

Synaptic processes and immune-related pathways implicated in Tourette syndrome.

Tourette syndrome (TS) is a neuropsychiatric disorder of complex genetic architecture involving multiple interacting genes. Here, we sought to elucidate the pathways that underlie the neurobiology of the disorder through genome-wide analysis. We analyzed genome-wide genotypic data of 3581 individuals with TS and 7682 ancestry-matched controls and investigated associations of TS with sets of genes that are expressed in particular cell types and operate in specific neuronal and glial functions. We employed a self-contained, set-based association method (SBA) as well as a competitive gene set method (MAGMA) using individual-level genotype data to perform a comprehensive investigation of the biological background of TS. Our SBA analysis identified three significant gene sets after Bonferroni correction, implicating ligand-gated ion channel signaling, lymphocytic, and cell adhesion and transsynaptic signaling processes. MAGMA analysis further supported the involvement of the cell adhesion and trans-synaptic signaling gene set. The lymphocytic gene set was driven by variants in FLT3, raising an intriguing hypothesis for the involvement of a neuroinflammatory element in TS pathogenesis. The indications of involvement of ligand-gated ion channel signaling reinforce the role of GABA in TS, while the association of cell adhesion and trans-synaptic signaling gene set provides additional support for the role of adhesion molecules in neuropsychiatric disorders. This study reinforces previous findings but also provides new insights into the neurobiology of TS.

Digenic mutations in severe congenital neutropenia.

Severe congenital neutropenia a clinically and genetically heterogeneous disorder. Mutations in different genes have been described as causative for severe neutropenia, e.g. ELANE, HAX1 and G6PC3. Although congenital neutropenia is considered to be a group of monogenic disorders, the phenotypic heterogeneity even within the yet defined genetic subtypes points to additional genetic and/or epigenetic influences on the disease phenotype. We describe congenital neutropenia patients with mutations in two candidate genes each, including 6 novel mutations. Two of them had a heterozygous ELANE mutation combined with a homozygous mutation in G6PC3 or HAX1, respectively. The other 2 patients combined homozygous or compound heterozygous mutations in G6PC3 or HAX1 with a heterozygous mutation in the respective other gene. Our results suggest that digenicity may underlie this disorder of myelopoiesis at least in some congenital neutropenia patients.

Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1.

Children with neurofibromatosis type 1 (NF-1), being constitutionally deficient for one allele of the NF1 gene, are at greatly increased risk of juvenile myelomonocytic leukemia (JMML). NF1 is a negative regulator of RAS pathway activity, which has a central role in JMML. To further clarify the role of biallelic NF1 gene inactivation in the pathogenesis of JMML, we investigated the somatic NF1 lesion in 10 samples from children with JMML/NF-1. We report that two-thirds of somatic events involved loss of heterozygosity (LOH) at the NF1 locus, predominantly caused by segmental uniparental disomy of large parts of chromosome arm 17q. One-third of leukemias showed compound-heterozygous NF1-inactivating mutations. A minority of cases exhibited somatic interstitial deletions. The findings reinforce the emerging role of somatic mitotic recombination as a leukemogenic mechanism. In addition, they support the concept that biallelic NF1 inactivation in hematopoietic progenitor cells is required for transformation to JMML in children with NF-1.

Mutations in the amiloride-sensitive epithelial sodium channel in patients with cystic fibrosis-like disease.

We investigated whether mutations in the genes that code for the different subunits of the amiloride-sensitive epithelial sodium channel (ENaC) might result in cystic fibrosis (CF)-like disease. In a small fraction of the patients, the disease could be potentially explained by an ENaC mutation by a Mendelian mechanism, such as p.V114I and p.F61L in SCNN1A. More importantly, a more than three-fold significant increase in incidence of several rare ENaC polymorphisms was found in the patient group (30% vs. 9% in controls), indicating an involvement of ENaC in some patients by a polygenetic mechanism. Specifically, a significantly higher number of patients carried c.-55+5G>C or p.W493R in SCNN1A in the heterozygous state, with odds ratios (ORs) of 13.5 and 2.7, respectively.The p.W493R-SCNN1A polymorphism was even found to result in a four-fold more active ENaC channel when heterologously expressed in Xenopus laevis oocytes. About 1 in 975 individuals in the general population will be heterozygous for the hyperactive p.W493R-SCNN1A mutation and a cystic fibrosis transmembrane conductance regulator (CFTR) gene that results in very low amounts (0-10%) functional CFTR. These ENaC/CFTR genotypes may play a hitherto unrecognized role in lung diseases.

Familial thrombocytosis caused by the novel germ-line mutation p.Pro106Leu in the MPL gene.

Familial thrombosis (FT) has been described as a rare autosomal-dominant disorder, mostly caused by activating mutations of the thrombopoietin gene (THPO). Other cases of FT have been linked to one of two different germline mutations in the myeloproliferative leukaemia virus oncogene gene (MPL), which codes for the thrombopoietin receptor MPL. We studied an Arab family with two siblings with severe thrombocytosis by linkage analysis and obtained evidence for linkage to MPL. Sequencing revealed homozygosity for the novel MPL germline mutation p.Pro106Leu (c.317C > T) in the two siblings. Subsequently, homozygosity for p.Pro106Leu was identified in six further FT patients from three other Arab families. Of 18 heterozygous carriers, 14 had normal platelet counts, while four had mild thrombocytosis. Strong support for association of the novel MPL mutation p.Pro106Leu with development of familial thrombocytosis has been obtained. Overall, p.Pro106Leu was absent on 386 alleles of 193 healthy German controls and present on 14 of 426 alleles (3.3%) of 213 unrelated Arabs, which was statistically significantly different (P < 0.001, Fisher's exact test). We assume that p.Pro106Leu is a frequent MPL mutation in the Arab population, leading to severe thrombocytosis in homozygotes and occasionally to mild thrombocytosis in heterozygotes. In the families described the mode of inheritance could be regarded as autosomal-recessive with possible mild heterozygote manifestation rather than autosomal-dominant with high penetrance as usually seen in FT.

A novel approach to CFTR mutation testing by pyrosequencing-based assay panels adapted to ethnicities.

BACKGROUND: Cystic fibrosis (CF) is a common autosomal recessive genetic disorder caused by a variety of sequence alterations in the CFTR gene [cystic fibrosis transmembrane conductance regulator (ATP-binding cassette sub-family C, member 7)]. Because the relative prevalence of mutations strongly depends on the ethnic background, first-level testing of CF as defined by recent consensus recommendations ought to be adaptable to the ethnicity of patients. METHODS: We therefore developed and implemented a diagnostic approach to first-level testing for CF based on published mutation frequencies and Pyrosequencing (PSQ) technology that we complemented with standard procedures of mutation detection at the second level. RESULTS: The current test system of PSQ assays for 46 target CF mutations [including CFTRdele2,3 (21 kb) and 1342-6 (T)(n) (5T/7T/9T)] permits recombinations of single assays to optimize sensitivities for certain ethnicities. By easy expansion of the original mutation panel, the first-level test sensitivities with other ethnic groups would be increased, provided that the mutation frequencies are known. The test was validated with our local, ethnically mixed, but mainly German population (155 patients). The mutation-detection rate for the 92 patients whose CF was confirmed by the sweat test was 89.0% for the patients of German descent (73 of the 92 patients) and 73.7% for the patients of any other origin (19 of the 92 patients). Ethnicity-adapted testing panels for our foreign CF patients would increase the sensitivities for the respective groups by approximately 5%. CONCLUSIONS: PSQ-based genotyping is a reliable, convenient, highly flexible, and inexpensive alternative to conventional methods for first-level testing of CFTR, facilitating flexible adaptation of the analyzed mutation panel to any local ethnic group.

No association between CALCA polymorphisms and clinical outcome or serum procalcitonin levels in German polytrauma patients.

PURPOSE: Procalcitonin (PCT) is accepted to be a relevant prognostic marker for the development of clinical complications in multiple trauma patients. Therefore, a prospective cohort study was conducted to investigate whether polymorphisms in the calcitonin (CALCA) gene are associated with PCT levels and posttraumatic complications. METHODS: During a 14day observation period, blood samples were drawn once daily for systemic PCT concentrations in multiple trauma patients (Injury Severity Score >16). For analysis of allele frequencies, genotype distribution and PCT concentrations polytraumatized patients were separated, according to the development of SIRS, sepsis, septic shock, ARDS, MODS and mortality. Furthermore, association between CALCA polymorphisms and PCT plasma concentrations was assessed. RESULTS: One hundred thirty seven patients with a mean ISS of 29.2+/-12.1 were included. When trauma patients were grouped according to different posttraumatic complications no association with CALCA SNPs was observed. Additionally, no association was found between CALCA polymorphisms and systemic PCT levels. CONCLUSION: CALCA polymorphisms are unlikely to influence clinical outcome in polytraumatized patients. Effects of microbial and inflammatory mediators, as well as other risk factors (gender, age, etc.) seem to have a more significant influence on the transcriptional regulation of CALCA and on PCT plasma concentrations than CALCA polymorphisms.

Interrogating the Genetic Determinants of Tourette's Syndrome and Other Tic Disorders Through Genome-Wide Association Studies.

OBJECTIVE: Tourette's syndrome is polygenic and highly heritable. Genome-wide association study (GWAS) approaches are useful for interrogating the genetic architecture and determinants of Tourette's syndrome and other tic disorders. The authors conducted a GWAS meta-analysis and probed aggregated Tourette's syndrome polygenic risk to test whether Tourette's and related tic disorders have an underlying shared genetic etiology and whether Tourette's polygenic risk scores correlate with worst-ever tic severity and may represent a potential predictor of disease severity. METHODS: GWAS meta-analysis, gene-based association, and genetic enrichment analyses were conducted in 4,819 Tourette's syndrome case subjects and 9,488 control subjects. Replication of top loci was conducted in an independent population-based sample (706 case subjects, 6,068 control subjects). Relationships between Tourette's polygenic risk scores (PRSs), other tic disorders, ascertainment, and tic severity were examined. RESULTS: GWAS and gene-based analyses identified one genome-wide significant locus within FLT3 on chromosome 13, rs2504235, although this association was not replicated in the population-based sample. Genetic variants spanning evolutionarily conserved regions significantly explained 92.4% of Tourette's syndrome heritability. Tourette's-associated genes were significantly preferentially expressed in dorsolateral prefrontal cortex. Tourette's PRS significantly predicted both Tourette's syndrome and tic spectrum disorders status in the population-based sample. Tourette's PRS also significantly correlated with worst-ever tic severity and was higher in case subjects with a family history of tics than in simplex case subjects. CONCLUSIONS: Modulation of gene expression through noncoding variants, particularly within cortico-striatal circuits, is implicated as a fundamental mechanism in Tourette's syndrome pathogenesis. At a genetic level, tic disorders represent a continuous spectrum of disease, supporting the unification of Tourette's syndrome and other tic disorders in future diagnostic schemata. Tourette's PRSs derived from sufficiently large samples may be useful in the future for predicting conversion of transient tics to chronic tic disorders, as well as tic persistence and lifetime tic severity.

No association of CNR1 gene variations with susceptibility to schizophrenia.

Schizophrenia is one of the most common psychiatric disorders. There is a growing body of evidence associating dysregulation of the endogenous cannabinoid system with the pathogenesis of schizophrenia. In order to test the hypothesis that mutations in the central cannabinoid receptor-1 (CNR1) gene confer susceptibility to the development of schizophrenia, we performed an association study in a group of 104 German patients with schizophrenia and 140 healthy controls, using three polymorphisms within and flanking the coding exon of CNR1 (rs6454674, rs1049353, AL136096). In addition, we analyzed the whole coding region of the CNR1 gene of 50 of the patients by capillary sequencing to detect rare mutations. Our adequately powered study failed to reveal a statistically significant segregation of CNR1 polymorphisms to the diseased or control group. Furthermore, capillary sequencing of CNR1 in a subgroup of study subjects did not show any non-synonymous mutations predicting malfunction of CNR1 in patients with schizophrenia. In conclusion, we could not detect a statistically significant association between mutations in the CNR1 gene and the predisposition to develop schizophrenia. However, further studies are necessary to unravel the relationship between mutations in the CNR1 gene and the genetic susceptibility for the manifestation of certain subtypes or schizophrenia i.e. the predominance of negative or positive symptoms or as predictors of the clinical course.

Hereditary hemorrhagic telangiectasia. Genetics, pathogenesis, clinical manifestation and management.

Hereditary hemorrhagic telangiectasia HHT, Morbus Osler or Osler-Weber-Rendu syndrome OMIM 187300, is an autosomal dominant disorder characterized by epistaxis, telangiectasia, multi-systemic vascular dysplasia and clinical presentation of wide variation. The pathogenesis involves dilated post-capillary venules or telangiectases in the mucus membrane of various organs as well as larger arteriovenous malformations. Genetic heterogeneity of HHT is confirmed; 2 disease loci, ACVRL1 and ENG genes, have been identified and characterized. The 2 major types of the disease, HHT1 and HHT2, are attributed to mutations in the ENG and ACVRL1 genes. ENG and ACVRL1 genes code for proteins, namely endoglin and activin-receptor-like kinase 1 ALK-1, which are members of the TGF-beta receptor family, are essential for maintaining vascular integrity. Another gene has been implicated in HHT; the HHT3 locus linked to chromosome 5. In the last 2 decades, the genetics, pathogenesis, clinical manifestations and management of HHT have been extensively researched. At this stage, it is deemed appropriate to review the wealth of information accumulated on the topic. Better understanding of the functions of endoglin, ALK-1, and other proteins involved in the pathogenesis of HHT should facilitate better management of patients with this disorder.