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We report upon PanelDesign, a framework to support the design of diagnostic next generation DNA sequencing panels with epidemiological information. Two publicly available resources, namely Genomics England PanelApp and Orphadata, were combined into a single data set to allow genes in a given NGS panel to be ranked according to the frequency of the associated diseases, thereby highlighting potential core genes as defined by the Eurogenetest/ESHG guidelines for diagnostic next generation DNA sequencing. In addition, PanelDesign can be used to evaluate the contribution of different genes to a given disease following ACMG (American College of Medical Genetics) technical standards.

The nodal cascade influences the development of bodily asymmetries in humans and other vertebrates. The gene PCSK6 has shown a regulatory function during left-right axis formation and is therefore thought to influence bodily left-right asymmetries. However, it is not clear if variation in this gene is also associated with structural asymmetries in the brain. We genotyped an intronic 33bp PCSK6 variable number tandem repeat (VNTR) polymorphism that has been associated with handedness in a cohort of healthy adults. We acquired T1-weighted structural MRI images of 320 participants and defined cortical surface and thickness for each HCP region. The results demonstrate a significant association between PCSK6 VNTR genotypes and gray matter asymmetry in the superior temporal sulcus, which is involved in voice perception. Heterozygous individuals who carry a short (≤ 6 repeats) and a long (≥ 9 repeats) PCSK6 VNTR allele show stronger rightward asymmetry. Further associations were evident in the dorsolateral prefrontal cortex. Here, individuals homozygous for short alleles show a more pronounced asymmetry. This shows that PCSK6, a gene that has been implicated in the ontogenesis of bodily asymmetries by regulating the nodal cascade, is also relevant for structural asymmetries in the human brain.

With the Act on Genetic Testing (GenDG), the German legislator has issued far-reaching regulations for human genetic services, including genetic counseling. This paper presents data on the use of human genetic counseling in the years before and after the entry into force of GenDG in order to provide an informed assessment of the possible effects of the law.Over a period of 13 years (2005 to 2017), the human genetic counseling services provided within the framework of the statutory health insurance and billable by EBM via the Kassenärztliche associations were recorded via a database query at the Central Institute of the National Association of Statutory Health Insurance Physicians (ZI-KBV) and via individual Kassenärztliche Vereinigungen Deutschlands. For the discussion of the observable development of using genetic counseling and possible future development, additional data on the referral behavior, the waiting times, processing time, and reasons for consultations were extracted from the GenBIn database.Demand for genetic counseling has steadily increased at an average rate of approximately 6% per year since 2009. This increase started well before the enactment of the GenDG and may be attributed to a multiplicity of factors. Change in demand for genetic counseling is characterized by increasing self-referrals and by increasing referrals by specialists other than obstetricians/gynecologists. Waiting times between 2011 and 2016/2017 have increased. While demand has been growing, the number of key service providers, the contracted medical specialists in human genetics, has remained almost constant. It is foreseeable that capacity limits will be reached if both trends continue.

ZusammenfassungDie neu überarbeiteten Leitlinien Chorea/Morbus Huntington geben auf S2k Niveau einen Überblick über den Stand der Forschung zum Erkrankungsverlauf sowie zu neuen Ansätzen der symptomatischen und verlaufsmodifizierenden Therapie bei der Huntington-Krankheit. Im Gegensatz zu vielen anderen Leitlinien bevorzugen die Autoren aus den deutschsprachigen Ländern als Erstlinienbehandlung der Chorea Tiaprid. Aufgrund von Nebenwirkungen, welche unter Tetrabenazin auftreten können – wie etwa Depression oder Akathisie, ist es gängige Praxis, Tetrabenazin erst in zweiter Linie einzusetzen. Die Leitlinien nehmen Stellung zu rechtlichen Fragen der Präimplantationsdiagnostik (PID) und der pränatalen Diagnostik (PD) in Deutschland, Österreich und der Schweiz sowie zu den Unterschieden zwischen dem prädiktiven und dem differenzialdiagnostischen Einsatz der molekulargenetischen Diagnostik. In den Leitlinien wird darüber hinaus sehr ausführlich zu den möglichen Differenzialdiagnosen bei einer Chorea ungeklärter Ätiologie Stellung genommen.

Autonomously replicating vectors represent a simple and versatile model system for genetic modifications, but their localization in the nucleus and effect on endogenous gene expression is largely unknown. Using circular chromosome conformation capture we mapped genomic contact sites of S/MAR-based replicons in HeLa cells. The influence of cis-active sequences on genomic localization was assessed using replicons containing either an insulator sequence or an intron. While the original and the insulator-containing replicons displayed distinct contact sites, the intron-containing replicon showed a rather broad genomic contact pattern. Our results indicate a preference for certain chromatin structures and a rather non-dynamic behaviour during mitosis. Independent of inserted cis-active elements established vector molecules reside preferentially within actively transcribed regions, especially within promoter sequences and transcription start sites. However, transcriptome analyses revealed that established S/MAR-based replicons do not alter gene expression profiles of host genome. Knowledge of preferred contact sites of exogenous DNA, e.g. viral or non-viral episomes, contribute to our understanding of episome behaviour in the nucleus and can be used for vector improvement and guiding of DNA sequences to specific subnuclear sites.

We present a prospective study of counselees seeking predictive testing for Huntington's disease at the Huntington Center North Rhine-Westphalia (Bochum, Germany) between 2010 and 2012. The aim was to observe the decision-making process of at-risk individuals and explore their experiences following the decision as well as the impacts of positive and negative mutation results. Data were collected using two standardized questionnaires as well as via a semi-standardized telephone interview one year after the initial counseling session. Seventy-two individuals participated in at least one of the three phases of the survey, including 31 individuals in the telephone interview. Sociodemographic data were in accordance with previous reports. The process of predictive testing was generally perceived in a positive manner, with almost all interviewees reporting a balanced emotional state one year after initial counseling, regardless of the decision for or against the test. The most important reasons named in favor of or against testing were assembled as well as different aspects regarding the satisfaction with the reached decision. In line with and expanding previous observations on gender-related differences in decision-making, our results suggest that gender-related aspects should be more strongly taken into account in genetic counseling during the predictive testing and counseling processes.

Cognitive control processes play an essential role not only in controlling actions but also in guiding attentional selection processes. Interestingly, these processes are strongly affected by organizational principles of the cerebral cortex and related functional asymmetries, but the neurobiological foundations are elusive. We ask whether neurobiological mechanisms that affect functional cerebral asymmetries will also modulate effects of top-down control processes on functional cerebral asymmetries. To this end, we examined potential effects of the imprinted gene leucine-rich repeat transmembrane neuronal 1 (LRRTM1) on attentional biasing processes in a forced attention dichotic listening task in 983 healthy adult participants of Caucasian descent using the "iDichotic smartphone app." The results show that functional cerebral asymmetries in the language domain are associated with the rs6733871 LRRTM1 polymorphism when cognitive control and top-down attentional mechanisms modulate processes in bottom-up attentional selection processes that are dependent on functional cerebral asymmetries. There is no evidence for an effect of LRRTM1 on functional cerebral asymmetries in the language domain unrelated to cognitive control processes. The results suggest that cognitive control processes are an important factor to consider when being interested in the molecular genetic basis of functional cerebral architecture.

Relative telomere length (TL) is regarded as a biomarker of biological age. Accelerated immune aging, as represented by TL reduction, has been demonstrated in autoimmune diseases, including multiple sclerosis (MS). However, it is still unresolved whether telomere shortening is the cause or the consequence of the pathogenic events underlying autoimmunity. Assessing TL in whole blood DNA samples in 138 MS patients and 120 healthy controls showed reduced TL in patients as compared with controls There seems to be a prelude of accelerated telomere shortening, which may increase the risk for development of MS.

Action control is achieved through a multitude of cognitive processes. One of them is the ability to inhibit responses, for which the dopaminergic systems is known to play an important role. Many lines of psychophysiological research substantiate that two distinct response inhibition subprocesses exist, but it has remained elusive whether they can be attributed to distinct neurobiological factors governing the dopaminergic system. We, therefore, investigated this question by examining the effects of DRD1 (rs4532) and DRD2 (rs6277) receptor polymorphisms on electrophysiological correlates of response inhibition subprocesses (i.e., Nogo-N2 and Nogo-P3) in 195 healthy human subjects with a standard Go/Nogo task. The results show that response inhibition performance at a behavioral level is affected by DRD1 and DRD2 receptor variation. However, from an electrophysiological point of view these effects emerge via different mechanisms selectively affected by DRD1 and DRD2 receptor variation. While the D1 receptor system is associated with pre-motor inhibition electrophysiological correlates of response inhibition processes (Nogo-N2), the D2 receptor system is associated with electrophysiological correlates of outcome evaluation processes. Dissociable cognitive-neurophysiological subprocesses of response inhibition are hence attributable to distinct dopamine receptor systems.

Eosinophilic granulomatosis with polyangiitis (EGPA: formerly Churg-Strauss syndrome) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasm antibodies (ANCA) specific for myeloperoxidase (MPO). We performed a genome-wide association study (GWAS) of EGPA, testing 7.5 million genetic variants in 684 cases and 6,838 controls. Case-control analyses were performed for EGPA as a whole, and stratified by ANCA. To increase power, we used a conditional false discovery rate method to leverage findings from GWASs of related phenotypes. In total, 11 variants were associated with EGPA, two specifically with ANCA-negative EGPA, and one (HLA-DQ) with MPO+ANCA EGPA. Many variants were associated with asthma, eosinophilic and immune-mediated diseases and, strikingly, nine were associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia underlies EGPA susceptibility. We demonstrate that EGPA comprises two genetically and clinically distinct syndromes, with ANCA-negative EGPA genetically more similar to asthma. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an MHC association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Five identified candidate genes are targets of therapies in development, supporting their exploration in EGPA.

INTRODUCTION Mutations in the BICD2 gene are causative for an autosomal dominant form of spinal muscular atrophy (SMALED2). Further, BICD2 mutations have been implicated in hereditary spastic paraplegia (HSP), but only very few such patients have been described. In this report we aimed to investigate the frequency of BICD2 mutations in patients with HSP and hereditary motor and sensory neuropathy (HMSN) who were negative for the most common known genetic causes. METHODS The cohorts comprised 171 HSP and 189 HMSN patients. Mutational analysis was performed with high-resolution melting analysis followed by Sanger sequencing. RESULTS In both cohorts, we found no known or likely pathogenic mutations in the BICD2 gene. DISCUSSION BICD2 mutations appear rather unlikely to cause a phenotype of HMSN and are a very rare cause of the HSP phenotype. Muscle Nerve 59:484-486, 2019.

Myelination of axons in the central nervous system is critical for human cognition and behavior. The predominant protein in myelin is proteolipid protein—making PLP1, the gene that encodes for proteolipid protein, one of the primary candidate genes for white matter structure in the human brain. Here, we investigated the relation of genetic variation within PLP1 and white matter microstructure as assessed with myelin water fraction imaging, a neuroimaging technique that has the advantage over conventional diffusion tensor imaging in that it allows for a more direct assessment of myelin content. We observed significant asymmetries in myelin water fraction that were strongest and rightward in the parietal lobe. Importantly, these parietal myelin water fraction asymmetries were associated with genetic variation in PLP1. These findings support the assumption that genetic variation in PLP1 affects white matter myelination in the healthy human brain.

Handedness is a multifactorial trait, and genes contributing to the differentiation of the left-right axis during embryogenesis have been identified as a major gene group associated with this trait. The methyltransferase SETDB2 (SET domain, bifurcated 2) has been shown to regulate structural left-right asymmetry in the vertebrate central nervous system by suppressing fgf8 expression. Here, we investigated the relation of genetic variation in SETDB2-and its paralogue SETDB1-with different handedness phenotypes in 950 healthy adult participants. We identified a haplotype on SETDB2 for which homozygous individuals showed a significantly lower lateralization quotient for handedness than the rest of the cohort after correction for multiple comparisons. Moreover, direction of handedness was significantly associated with genetic variation in this haplotype. This effect was mainly, but not exclusively, driven by the sequence variation rs4942830, as individuals homozygous for the A allele of this single nucleotide polymorphism had a significantly lower lateralization quotient than individuals with at least one T allele. These findings further confirm a role of genetic pathways relevant for structural left-right axis differentiation for functional lateralization. Moreover, as the protein encoded by SETDB2 regulates gene expression epigenetically by histone H3 methylation, our findings highlight the importance of investigating the role of epigenetic modulations of gene expression in relation to handedness.

Hyperuricemia is very common in industrialized countries and known to promote vascular smooth muscle cell proliferation. Juvenile hyperuricemia is a hallmark of uromodulin-associated kidney disease characterized by progressive interstitial renal fibrosis leading to end-stage renal disease within decades. Here we describe a member of a Polish-German family with a history of familial background of chronic kidney disease, hyperuricemia, and gout. This patient had hypertension because of bilateral small renal arteries, hyperuricemia, and chronic kidney disease. Clinical and molecular studies were subsequently performed in 39 family members, which included a physical examination, Duplex ultrasound of the kidneys, laboratory tests for renal function, and urine analysis. In eight family members contrast-enhanced renal artery imaging by computed tomography–angiography or magnetic resonance imaging was conducted and showed that bilateral non-arteriosclerotic small caliber renal arteries were associated with hyperuricemia and chronic kidney disease. Of the 26 family members who underwent genotyping, 11 possessed the P236R mutation (c.707C>G) of the uromodulin gene. All family members with a small caliber renal artery carried the uromodulin P236R mutation. Statistical analysis showed a strong correlation between reduced renal artery lumen and decreased estimated glomerular filtration rate. Thus, bilateral small caliber renal arteries are a new clinical phenotype associated with an uromodulin mutation.

Summary Variations in two genes of the tumour necrosis factor (TNF) alpha pathway have been implicated in the pathogenesis of autoimmune diseases: polymorphisms in the TNFRSF1A gene, encoding TNF receptor 1, showed significant association with MS in genomewide association scans, and variation in or near the TNFAIP3 gene, coding for a negative regulator of NFkB, was associated with MS, systemic lupus erythematosus, diabetes and rheumatoid arthritis. This study aimed at investigating association of MS with variation in the TNFRSF1A gene as well as in the TNFAIP3 gene region in an independent German case–control cohort. Four hundred and ninety-seven unrelated patients with MS and 878 healthy controls were genotyped with restriction enzyme digestion or TaqMan assays for three polymorphisms in the TNFRSF1A gene and seven in the region of the TNFAIP3 gene. Allele, genotype and haplotype frequencies were compared between cases and controls by chi-square testing. We found significant association of rs10499194, located in the intergenic region upstream of TNFAIP3, with MS (pc = 3.4 × 10−4). Further, the intronic SNP rs1800693 in TNFRSF1A showed moderate association (pc = 0.033) with MS. In conclusion, evidence is accumulating that polymorphisms in both TNFAIP3 and TNFRSF1A genes play a role in MS pathogenesis. Additional studies are warranted to further elucidate the role of TNF pathway variation for MS development.

Background Neurodegeneration with brain iron accumulation (NBIA) comprises a clinically and genetically heterogeneous group of diseases presenting with movement disorders and brain iron deposits. In addition to NBIA subtypes caused by mutations in PANK2 and PLA2G6, mutations in the C19orf12 gene were recently described as the third frequent cause of NBIA (called mitochondrial membrane protein-associated neurodegeneration, MPAN). Additionally, the X-linked gene WDR45 was found causative for a special subtype named static encephalopathy in childhood with neurodegeneration in adulthood (also called BPAN); however, analysis of this gene in a broader spectrum of NBIA has not been reported yet. Methods In a heterogeneous cohort of 69 patients with suspected NBIA that did not carry mutations in PANK2 and PLA2G6, the coding region of C19orf12 was evaluated by Sanger sequencing. The WDR45 gene was analyzed via high resolution melting and subsequent sequence analysis. Results Previously described homozygous C19orf12 mutations were found in 3/69 NBIA patients (4.3%). Analysis of the WDR45 gene revealed a novel heterozygous missense mutation in one female NBIA patient showing psychomotor retardation with secondary decline. Conclusions C19orf12 mutations were confirmed in our heterogeneous NBIA cohort, while WDR45 mutations appear to be restricted to the subtype showing encephalopathy in childhood with neurodegeneration in adulthood.

Intellectual disability (ID) is one of the most common reasons for referral to genetic counseling. Nevertheless, in over 50% of the cases no diagnosis can be made. Here, we present how exome sequencing in combination with medical genetics evaluation led to the identification of a known pathogenic homozygous mutation in MAN1B1 in a consanguineous Turkish family. The phenotype comprised mild ID, truncal obesity and facial dysmorphism, comparable to that of the patients in the 3 recent publications on mutations in this gene. Clinically, the majority of patients in the literature showed congenital disorder of glycosylation syndrome type 2. In this study, we summarize the current knowledge about MAN1B1 mutations from the literature as well as databases and suggest that exome sequencing should be implemented in a larger scale in routine diagnostics, since autosomal recessive ID has proven to be extremely heterogeneous. Even syndromic patterns may only become recognizable retrospectively.

Background: The discovery of the mutation causing Huntington’s disease (HD) in 1993 allowed direct mutation analysis and predictive testing to identify currently unaffected carriers with a sensitivity and specificity of virtually 100%. Objective: The present study was designed to comprehensively profile the participants who sought predictive testing for HD between 1993 and 2009 in our Huntington centre. Methods: Using a retrospective design, we analysed the written documentation of the counselling sessions for all referrals for predictive mutation testing in this time span. Six hundred sixty-three individuals at risk for HD requested predictive testing. Roughly half (n = 333) completed the protocol and received their test result. Results: In general our findings are in accordance with other reports: most participants share an a priori risk of 50% (91.1%); more females request testing (58.5%); and those who ask for the result are mostly in their 30 s (mean = 35.1 years). Of those at 50% or 25% prior risks, 47.4% and 22.7%, respectively, tested positive in accordance with the respective risk of inheriting HD. Generally, more participants with an affected mother than father sought genetic testing (52.5% versus 47.5%). Interestingly, this difference was especially evident in the group of females who finally withdrew from testing (59.1%, p = 0.040). Men, in particular those who decided in favour of the test, were more often accompanied by their partner in the pre-test counselling session than vice versa (67.9% versus 44.7%, p = 0.003). On the other hand, significantly more men who were being tested did not have a companion in the pre-test session as compared with men who decided against the test (40.0% versus 25.7%, p = 0.012). During the first four years of predictive testing (1993–1996) more participants completed the protocol and received their test result as in later years. Yet, in this early time span significantly fewer females finally decided in favour of the test (48.4%, p = 0.005). These findings are discussed longitudinally and in the context of the experience in other centres. Conclusions: We present new gender-specific aspects of decision-making for predictive HD tests.

Acrocallosal syndrome (ACLS) is a rare autosomal recessive disorder characterized by agenesis of the corpus callosum, facial dysmorphism, postaxial polydactyly of the hands as well as preaxial polydactyly of the feet, and developmental delay. Mutations in the KIF7 gene, encoding a molecule within the Sonic hedgehog (SHH) pathway, have been identified as causative for ACLS but also for the fatal hydrolethalus syndrome and some cases of Joubert syndrome. We report here on a Tunisian boy who shows the clinical characteristics of ACLS and was found to have a novel homozygous KIF7 nonsense mutation. Further, we summarize the current knowledge about the clinical spectrum associated with KIF7 mutations as well as genetic and/or phenotypic overlap with ciliopathies and other mutations in the SHH pathway.

The corpus callosum is the brain's largest commissural fiber tract and is crucial for interhemispheric integration of neural information. Despite the high relevance of the corpus callosum for several cognitive systems, the molecular determinants of callosal microstructure are largely unknown. Recently, it was shown that genetic variations in the myelin-related proteolipid 1 gene PLP1 and the axon guidance related contactin 1 gene CNTN1 were associated with differences in interhemispheric integration at the behavioral level. Here, we used an innovative new diffusion neuroimaging technique called neurite orientation dispersion and density imaging (NODDI) to quantify axonal morphology in subsections of the corpus callosum and link them to genetic variation in PLP1 and CNTN1. In a cohort of 263 healthy human adults, we found that polymorphisms in both PLP1 and CNTN1 were significantly associated with callosal microstructure. Importantly, we found a double dissociation between gene function and neuroimaging variables. Our results suggest that genetic variation in the myelin-related gene PLP1 impacts white matter microstructure in the corpus callosum, possibly by affecting myelin structure. In contrast, genetic variation in the axon guidance related gene CNTN1 impacts axon density in the corpus callosum. These findings suggest that PLP1 and CNTN1 gene variations modulate specific aspects of callosal microstructure that are in line with their gene function.

Huntington's disease (HD) is a monogenic inherited polyglutamine-mediated neurodegenerative disorder for which effective therapies are currently unavailable. Neuropeptide Y (NPY) has been implicated as a potential therapeutic target in several neurodegenerative diseases, including HD. However, its mechanisms of action in the context of HD pathology remain unknown. Here, we investigated the beneficial effects of Y2 receptor (Y2R) activation with NPY or Y2R selective agonist NPY13-36 in the R6/2 mouse and PC12 cell models of HD. Also, we explored the effects of selective pharmacological blockage of Y2R using selective non-peptide small molecule Y2R antagonist SF31 in vivo and in vitro. Our results showed that activation of Y2R with intranasal NPY or NPY13-36 led to an improved motor function in R6/2 mice as revealed by rotarod performance, vertical pole test, and hindlimb clasping behaviour. Also, intranasal NPY or NPY13-36 led to a decrease in aggregated mHtt and mediated increase in dopamine and cAMP-regulated phosphoprotein, 32kDa (DARPP-32), brain-derived neurotrophic factor (BDNF), and activated extracellular signal-regulated protein kinases (pERK1/2) levels in R6/2 mice. Intranasal NPY or NPY13-36 had no effect on body weight but showed positive effects on survival in R6/2 mice. Furthermore, intranasal NPY or NPY13-36 attenuated induction of proinflammatory cytokine and inflammatory mediators in R6/2 mice. In contrast, antagonizing by using SF31 exacerbates phenotypic severity in R6/2 mice and treatment effects with either intranasal NPY or NPY13-36 were significantly blocked.In vitro, using inducible PC12/HttQ103-EGFP cells, treatment with NPY or NPY13-36 protected against mHtt-mediated neuromorphological defects (neurite length and soma area) and neurotoxicity but had no effect on mHtt inclusion body formation. Conversely, co-treatment with SF31 significantly inhibited these effects. Together, our findings extend previous evidence of the beneficial effects of NPY in R6/2 mice, and more importantly, suggest that targeted activation of Y2R receptor might be a promising disease-modifying target for HD and other neurodegenerative diseases.

Molecular neurobiological factors determining corpus callosum physiology and anatomy have been suggested to be one of the major factors determining functional hemispheric asymmetries. Recently, it was shown that allelic variations in two myelin-related genes, the proteolipid protein 1 gene PLP1 and the contactin 1 gene CNTN1, are associated with differences in interhemispheric integration. Here, we investigated whether three single nucleotide polymorphisms that were associated with interhemispheric integration via the corpus callosum in a previous study also are relevant for functional hemispheric asymmetries. To this end, we tested more than 900 healthy adults with the forced attention dichotic listening task, a paradigm to assess language lateralization and its modulation by cognitive control processes. Moreover, we used the line bisection task, a paradigm to assess functional hemispheric asymmetries in spatial attention. We found that a polymorphism in PLP1, but not CNTN1, was associated with performance differences in both tasks. Both functional hemispheric asymmetries and their modulation by cognitive control processes were affected. These findings suggest that both left and right hemisphere dominant cognitive functions can be modulated by allelic variation in genes affecting corpus callosum structure. Moreover, higher order cognitive processes may be relevant parameters when investigating the molecular basis of hemispheric asymmetries.

Background Spinocerebellar ataxia (SCA) subtypes are often caused by expansions in non-coding regions of genes like SCA8, SCA10, SCA12 and SCA36. Other ataxias are known to be associated with repeat expansions such as fragile X-associated tremor ataxia syndrome (FXTAS) or expansions in the C9orf72 gene. When no mutation has been identified in the aforementioned genes next-generation sequencing (NGS)-based diagnostics may also be applied. In order to define an optimal diagnostic strategy, more information about the frequency and phenotypic characteristics of rare repeat expansion disorders associated with ataxia should be at hand. Methods We analyzed a consecutive cohort of 440 German unrelated patients with symptoms of cerebellar ataxia, dysarthria and other unspecific symptoms who were referred to our center for SCA diagnostics. They showed alleles in the normal range for the most common SCA subtypes SCA1-3, SCA6, SCA7 and SCA17. These patients were screened for expansions causing SCA8, SCA10, SCA12, SCA36 and FXTAS as well as for the pathogenic hexanucleotide repeat in the C9orf72 gene. Results Expanded repeats for SCA10, SCA12 or SCA36 were not identified in the analyzed patients. Five patients showed expanded SCA8 CTA/CTG alleles with 92-129 repeats. One 51-year-old male with unclear dementia symptoms was diagnosed with a large GGGGCC repeat expansion in C9orf72. The analysis of the fragile X mental retardation 1 gene (FMR1) revealed one patient with a premutation (>50 CGG repeats) and seven patients with alleles in the grey zone (41 to 54 CGG repeats). Conclusions Altogether five patients showed 92 or more SCA8 CTA/CTG combined repeats. Our results support the assumption that smaller FMR1 gene expansions could be associated with the risk of developing neurological signs. The results do not support genetic testing for C9orf72 expansion in ataxia patients.

Lateralization is a fundamental principle of nervous system organization but its molecular determinants are mostly unknown. In humans, asymmetric gene expression in the fetal cortex has been suggested as the molecular basis of handedness. However, human fetuses already show considerable asymmetries in arm movements before the motor cortex is functionally linked to the spinal cord, making it more likely that spinal gene expression asymmetries form the molecular basis of handedness. We analyzed genome-wide mRNA expression and DNA methylation in cervical and anterior thoracal spinal cord segments of five human fetuses and show development-dependent gene expression asymmetries. These gene expression asymmetries were epigenetically regulated by miRNA expression asymmetries in the TGF-β signaling pathway and lateralized methylation of CpG islands. Our findings suggest that molecular mechanisms for epigenetic regulation within the spinal cord constitute the starting point for handedness, implying a fundamental shift in our understanding of the ontogenesis of hemispheric asymmetries in humans. DOI: http://dx.doi.org/10.7554/eLife.22784.001

Sensory memory systems are modality-specific buffers that comprise information about external stimuli, which represent the earliest stage of information processing. While these systems have been the subject of cognitive neuroscience research for decades, little is known about the neurobiological basis of sensory memory. However, accumulating evidence suggests that the glutamatergic system and systems influencing glutamatergic neural transmission are important. In the current study we examine if functional promoter variations in neuropeptide Y (NPY) and its receptor gene NPY2R affect iconic memory processes using a partial report paradigm. We found that iconic memory decayed much faster in individuals carrying the rare promoter NPY2R G allele which is associated with increased expression of the Y2 receptor. Possibly this effect is due to altered presynaptic inhibition of glutamate release, known to be modulated by Y2 receptors. Altogether, our results provide evidence that the functionally relevant single nucleotide polymorphism (SNP) in the NPY2R promoter gene affect circumscribed processes of early sensory processing, i.e. only the stability of information in sensory memory buffers. This leads us to suggest that especially the stability of information in sensory memory buffers depends on glutamatergic neural transmission and factors modulating glutamatergic turnover.

Evaluation of: Damotte V, Guillot-Noel L, Patsopoulos NA et al. A gene pathway analysis highlights the role of cellular adhesion molecules in multiple sclerosis susceptibility. Genes Immun. 15(2), 126–132 (2014). This study represents a gene pathway analysis focusing on the role of cellular adhesion molecules (CAMs) for susceptibility to multiple sclerosis (MS). The authors focused on CAM genes, since CAMs play an important role in the disruption of the blood–brain barrier, an early important mechanism in MS pathogenesis. Data from eight genome-wide association studies (GWAS) were analyzed together with protein interaction network data, and hereby a total of 70 genes involved in the CAM pathway were investigated. The authors identified five subnetworks in which significantly associated CAM genes were over-represented, including among others ITGA4, coding for the target of natalizumab. Thus, the importance of genetic variation in CAM genes for MS pathogenesis and therapy was further underlined. However, it may take some time before these genetic results can become clinically relevant.

Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the HTT gene. Although the variation in age at onset (AO) is partly explained by the lengths of the expanded repeats, the unexplained variation is highly heritable, emphasizing the role of the so-called genetic background on disease expression. Neuropeptide Y (NPY) has been implicated in the modulation of neuroprotection, neurogenesis, and neuroinflammation. Therefore, the aim of the present study was to analyze different single nucleotide polymorphisms (SNPs) in order to test the possibility that genetic variation in NPY or three of its receptor genes (NPY1R, NPY2R, and NPY5R) may explain some of the variation in AO of HD motor manifestations, in a comprehensive cohort of 487 German HD patients. We found modest association of the AO with two NPY promoter variations and a highly significant association with a NPY2R promoter SNP (rs2234759; p = 0.0004). Investigating the functional impact of rs2234759 by luciferase assays revealed that the high-expression NPY2R genotypes were associated with later AO in HD. Additionally, treatment of PC12 cells expressing mutant huntingtin (htt) exon 1 with NPY and the NPY2R agonist NPY(3-36) has a protective effect against mutant htt-induced cell death. Thus, NPY might act through Y2 receptors to slow down the course of HD, and hence, this peptide could be of interest as a possible therapeutic agent.

Left-hemispheric language dominance is a well-known characteristic of the human language system, but the molecular mechanisms underlying this crucial feature of vocal communication are still far from being understood. The forkhead box P2 gene FOXP2, which has been related to speech development, constitutes an interesting candidate gene in this regard. Therefore, the present study was aimed at investigating effects of variation in FOXP2 on individual language dominance. To this end, we used a dichotic listening and a visual half-field task in a sample of 456 healthy adults. The FOXP2 SNPs rs2396753 and rs12533005 were found to be significantly associated with the distribution of correct answers on the dichotic listening task. These results show that variation in FOXP2 may contribute to the inter-individual variability in hemispheric asymmetries for speech perception.

Huntington disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the HTT gene. Although the variation in age at onset (AO) is partly explained by the length of the expanded repeat blocks, the unexplained variation in AO is highly heritable, emphasizing the role of modifier genes on disease expression. Since down-regulation of type 1 cannabinoid (CB1) receptors is a key pathogenic event in HD, it has been suggested that activation of these receptors in patients may attenuate disease progression. In order to evaluate whether variations in the cannabinoid receptor 1 (CNR1) gene encoding the CB1 receptor protein have modifying effects on the AO of HD, we performed an association study between CNR1 polymorphisms and AO in HD patients. A (AAT)n repeat and a total of nine single nucleotide polymorphisms (SNPs) in the CNR1 gene were selected for genotyping in a cohort of 473 German HD patients recruited in the Huntington Center NRW in Bochum. The AO was significantly associated with the longest alleles (≥17 AAT) of the (AAT)n repeat polymorphism downstream of the CNR1 gene (p = 0.007) as well as with one SNP in the 3′UTR of CNR1 (rs4707436, p = 0.05). Interestingly, the allelic variation of rs4707436 affects different microRNA (miRNA) binding sites which could alter gene regulation and consequently influence protein expression. These findings support the idea that CNR1 variation may have modifying effects on the AO in HD.

Objectives To investigate the contribution of genetic polymorphisms of toll like receptor (TLR) 9 and related genes on the susceptibility and clinical manifestation of anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitides (AAV). Methods Four single nucleotide polymorphisms (SNPs) in TLR9 were genotyped in 863 German AAV cases and 1344 healthy controls. Significant results were replicated in a cohort of 426 Dutch and British AAV cases. 11 polymorphisms in TLR9 related genes were studied concomitantly. Results A strong association of TLR9 genotypes and haplotypes with granulomatosis with polyangiitis was observed as well as a contrariwise association with microscopic polyangiitis. The association was confirmed when cases were compared according to ANCA status rather than to clinical entity. This was partly replicated in the second cohort leading to a striking overall difference in TLR9 allele/haplotype frequencies between proteinase 3 (PR3) ANCA+ and myeloperoxidase (MPO) ANCA+ cases (p=0.00000398, pc=0.000016, OR 1.68 (95% CI 1.35 to 2.1) for rs352140; p=0.000011, pc=0.000044, OR 1.64 (95% CI 1.31 to 2.04) for a 3-SNP haplotype). No significant association or epistatic effect was detected for TLR9 related genes: interleukin 6, interleukin 23 receptor, myeloid differentiation primary response 88, TNF receptor-associated factor 6, interleukin-1 receptor-associated kinase 4, discs large homolog 5 and nucleotide-binding oligomerisation domain containing 2. Conclusions We provide further evidence that PR3-ANCA+ AAV differs genetically from MPO-ANCA+ AAV. TLR9 signalling may be involved in disease pathology, favouring models of infectious agents triggering AAV development.

Single nucleotide polymorphisms (SNPs) in the serotonergic (5HT) system seem to have modulatory effects on depression and physical function. Preliminary evidence suggests that gene×environment interactions play a role in the development of depression, with somatic complaints serving as environmental stressors. We hypothesized that pain intensity may serve as a stress factor that modulates the association between SNPs in the 5HT system and depression. We investigated symptoms of pain, depression, physical functioning, and disability in 224 patients 6months after lumbar disc surgery. Associations between these variables and functional promoter SNPs in the serotonin receptor genes 5HTR1A (rs6295) and 5HTR2A (rs6311) were analyzed. For 5HTR2A, we found a significant gene×environment×sex interaction, as female patients carrying at least one A allele of the -1438A/G promoter SNP had significantly higher depression scores when confronted with severe pain compared to women harboring the GG genotype (P=.005). For 5HTR1A, patients homozygous for the -1019 G allele presented higher Beck Depression Inventory scores relative to the CG/CC group, indicating a major effect of this SNP on depression. Furthermore, women homozygous for either the 5HTR1A G allele or the 5HTR2A A allele had lower levels of physical functioning than patients with the other genotypes. These results suggest that 5HTR1A and 5HTR2A promoter variations have gender-dependent modulatory effects on depression and physical function in patients with pain. Furthermore, this study demonstrates that pain after lumbar surgery modulates the association between 5HT gene polymorphisms and depression.

Interhemispheric communication during demanding cognitive tasks shows pronounced interindividual variation. Differences in interhemispheric transfer time are constituted by the relative composition of slow and fast fibers. The speed of axonal conduction depends on the diameter of the axon and its myelination. To understand the possible genetic impact of myelin genes on performance in the Banich-Belger Task, a widely used paradigm to assess interhemispheric integration, 453 healthy adults were genotyped for 18 single nucleotide polymorphisms (SNPs) in six myelin-related candidate genes. We replicated the typical pattern of results in the Banich-Belger Task, supporting the idea that performance on cognitively demanding tasks is enhanced when cognitive processing is distributed across the two hemispheres. Moreover, allelic variations in the proteolipid protein 1 gene PLP1 and the contactin 1 gene CNTN1 correlated with the extent to which individual performance is enhanced by interhemispheric integration. Variation in myelin genes possibly affects the microstructure of the corpus callosum by altering oligodendrocyte structure. Therefore, these results provide a foundation for understanding how genetics plays a role in modulating the efficacy of transcallosal transmission.

Lipoid proteinosis (LP) is an autosomal recessive genodermatosis known to be caused by mutations in ECM1. Nonsense and missense mutations are the most common variations in LP. Up to date, only 6 splice site mutations have been observed. We report on a 26-year-old female LP patient from a Turkish consanguineous family carrying a novel homozygous splice site mutation in intron 8 of the ECM1 gene and summarize the current knowledge on ECM1 mutations and possible genotype-phenotype correlations.

Mutations in the senataxin (SETX) gene can cause amyotrophic lateral sclerosis 4 (ALS4), an autosomal dominant form of juvenile onset amyotrophic lateral sclerosis, or result in autosomal recessive ataxia with oculomotor apraxia type 2. Great caution regarding the possible disease causation, especially of missense variations, has to be taken. Here, we evaluated the significance of all previously reported SETX missense mutations as well as six newly identified variations in 54 patients suspected of having ALS4. Yet, epidemiologic and in silico evidence indicates that all newly identified variations and two previously published ALS4-related missense variations (C1554G and I2547T) are most likely non-pathogenic, demonstrating the problems of interpretation of SETX missense alleles in the absence of functional assays.

Appropriate attention levels are pivotal for cognitive processes, and individual differences in attentional functioning are related to variations in the interplay of neurotransmitters. The attention network theory reflects attention as a non-homogenous set of separate neural networks: alerting, orienting and conflicting. In the present study, the role of variations in GRIN2B, which encodes the NR2B subunit of N-methyl-d-aspartate (NMDA) receptors, was explored with regard to the regulation of arousal and attention by comparing the efficiency of the three attentional networks as measured with the Attention Network Test (ANT). Two synonymous SNPs in GRIN2B, rs1806201 (T888T) and rs1806191 (H1178H) were genotyped in 324 young Caucasian adults. Results revealed a highly specific modulatory influence of SNP rs1806201 on alerting processes with subjects homozygous for the frequent C allele displaying higher alerting network scores as compared to the other two genotype groups (CT and TT). This effect is due to the fact that in the no cue condition faster reaction times were evident in participants carrying at least one of the rare T alleles, possibly as a result of more effective glutamatergic neurotransmission. The results might be further explained by a dissociation between tonic and phasic alertness modulated by the GRIN2B genotype and by a ceiling effect, meaning that subjects cannot be phasicly alert in excess to a certain level. Altogether, the results show that variations in GRIN2B have to be taken into consideration when examining attentional processes.

Autosomal dominant proximal spinal muscular atrophy (ADSMA) is a rare disorder with unknown gene defects in the majority of families. Here we describe a family where the diagnosis of juvenile and adult onset ADSMA was made in three individuals. Because of retained tendon reflexes an atypical course of juvenile amyotrophic lateral sclerosis (ALS4) was considered. SETX gene sequencing revealed the previously reported heterozygous missense mutation c.1166T

Huntington’s disease (HD) is caused by the expansion of a CAG repeat within exon 1 of the huntingtin (HTT) gene. Although the variation in age at onset is partly explained by the lengths of the expanded repeat, the unexplained variation is heritable, emphasizing the role of the so-called genetic background on disease expression. Identification of modifier genes can confirm intracellular pathways already suspected to be involved in pathophysiological processes related to HD pathogenesis, but it may also point to completely new pathways and processes that have not yet been considered. Most importantly, confirmed modifier genes provide new targets for the development of therapies. Up to now, a wide range of susceptible HD modifier genes related to different biochemical pathways has been examined. On the basis of the published literature in this field, this review provides an overview of HD modifiers and integrates them into selected pathophysiology aspects.