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The genetic etiology of ALS includes few rare, large-effect variants and potentially many common, small-effect variants per case. The genetic risk liability for ALS might require a threshold comprised of a certain amount of variants. Here, we tested the degree to which risk for ALS was affected by rare variants in ALS genes, polygenic risk score, or both. 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by SNP-chip genotyping and targeted sequencing of known ALS genes. ALS GWAS summary statistics were used to estimate an ALS PRS. Cases and controls were subdivided into rare variant carriers and non-carriers. Risk for ALS was significantly associated with PRS and rare variants independently, but the interaction was not significant. ALS PRS affected risk only in those not carrying a rare variant, suggesting that rare variants in ALS genes are generally sufficient for disease risk. Rather than modifying the penetrance of rare variants, ALS PRS is most informative in the absence of these variants.

Previous studies using whole exome sequencing (WES) have shown that a significant proportion of adult patients with undiagnosed ataxia in European and North American cohorts have a known genetic cause. Little is known about the diagnostic yield of WES in non-Caucasian ataxic populations. Herein, we used WES to investigate a Brazilian cohort of 76 adult patients with idiopathic ataxia previously screened for trinucleotide expansions in known ataxia genes. We collected clinical and radiological data from each patient. WES was performed following standard procedures. Only variants labeled as pathogenic or likely pathogenic according to American college of medical genetics and genomics (ACMG) criteria were retrieved. We determined the diagnostic yield of WES for the whole cohort and also for subgroups defined according to presence or not of pyramidal signs, peripheral neuropathy, and cerebellar atrophy. There were 41 women and 35 men. Mean age at testing was 48 years. Pyramidal signs, peripheral neuropathy, tremor, and cerebellar atrophy were found in 38.1%, 13.1%, 10.5%, and 68.3% of all subjects, respectively. Diagnostic yield of WES was 35.5%. Thirty-six distinct mutations were found in 20 different genes, determining the diagnosis of 18 autosomal recessive and 9 autosomal dominant ataxias. SACS and SPG7 were the most frequently found underlying genes. WES performed better in the subgroup with vs the subgroup without spasticity (p = 0.005). WES was diagnostic in 35.5% of cases of the Brazilian cohort of ataxia cases. These results have implications for diagnosis, genetic counseling and eventually treatment.

Background Although the typical inheritance of spastic paraplegia 7 is recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant hereditary spastic paraplegia (HSP). Objectives We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of HSP patients and controls to examine the association of SPG7 and HSP. Methods We analyzed 585 HSP patients from 372 families and 1175 controls, including 580 unrelated individuals. Whole-exome sequencing was performed on 400 HSP patients (291 index cases) and all 1175 controls. Results The frequency of heterozygous pathogenic/likely pathogenic SPG7 variants (4.8%) among unrelated HSP patients was higher than among unrelated controls (1.7%; OR 2.88, 95% CI 1.24-6.66, P = 0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index patients versus 0.85% in unrelated controls (OR 4.42, 95% CI 1.49-13.07, P = 0.005). Similar results were obtained after including only genetically-undiagnosed patients. We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in known HSP genes, compared to zero in controls (OR 19.58, 95% CI 1.05-365.13, P = 0.0031), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2, and MORC2). Of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Conclusions Our results provide evidence for complex inheritance in SPG7-associated HSP, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance. © 2021 International Parkinson and Movement Disorder Society.

Background Spinocerebellar ataxia types 1, 2, 3 and Huntington disease are neurodegenerative disorders caused by expanded CAG repeats. Methods We performed an in-silico analysis of CAG repeats in ATXN1, ATXN2, ATXN3, and HTT using 30× whole-=genome sequencing data of 2504 samples from the 1000 Genomes Project. Results Seven HTT-positive, 3 ATXN2-positive, 1 ATXN3-positive, and 6 possibly ATXN1-positive samples were identified. No correlation was found between the repeat sizes of the different genes. The distribution of CAG alleles varied by ethnicity. Conclusion Our results suggest that there may be asymptomatic small expanded repeats in almost 0.5% of these populations. © 2020 International Parkinson and Movement Disorder Society.

Recently, the number of dinucleotide CA repeats in an intron of theHere, we used whole-genome sequencing and tested theWe find that repeats well above the previously reported pathogenic threshold of 19 are commonly observed in unaffected individuals across different populations. Furthermore, we did not observe an association between longerIn summary, our results do not support a role of

Restless legs syndrome (RLS) is a common neurological condition, with a prevalence of 5–15% in Central Europe and North America. Although genome-wide association studies (GWAS) have identified some common risk regions for RLS, the causal genes have yet to be fully elucidated. We conducted a transcriptome-wide association study involving 15,126 RLS cases and 95,725 controls, from the most recent meta-analysis of GWAS, and gene expression weights of GTEx v7 and the CMC dorsolateral prefrontal cortex tissue panels. We identified 13 associations (in 8 independent loci) at the transcriptome-wide significant level, of which 6 were not implicated in the previous GWAS: SKAP1, SLC36A1, CCDC57, FN3KRP, NCOA6/TRPC4AP. A fine-mapping approach prioritized CMTR1, RP1-153P14.5, PRPF6, and PPP3R1 – to our knowledge, the latter of which is the first RLS-associated gene directly implicated in dopaminergic pathways. Overall, our findings highlight the power of integrating gene expression data with GWAS to prioritize putative causal genes for functional follow-up studies., Fulya Akçimen et al. report a transcriptome-wide association study of restless legs syndrome using publicly available data from genome-wide association studies and gene expression data from GTEx. They find significant associations at 8 loci, 6 of which are novel and one of which implicates dopaminergic pathway.

Restless legs syndrome (RLS) is a common sleep-related sensory-motor disorder. It is characterized by uncomfortable sensations in the legs during the evening or at night. The symptoms can be partially relieved by movement, so typically affected individual needs to walk during rest time; this interferes with sleep. GWAS have identified 19 RLS-associated loci. Among the first to be reported and most significant and robustly replicated reports are variants in the SKOR1 noncoding regions. SKOR1 is highly expressed in the CNS of humans and mice. Skor1 acts as a corepressor of Lbx1 transcription factor in mice and these two genes act together to regulate the cell fate of interneurons in the dorsal horn of the spinal cord. Based on this data we investigated the regulatory role of SKOR1 using a global RNA-sequencing approach in human cell lines where SKOR1 was either overexpressed or silenced. For this work we generated and validated a new poly-clonal anti-SKOR1. Pathway and gene set enrichment analyses of the differentially expressed genes showed, among others, enrichment of genes involved in neurodevelopment and iron metabolism, two RLS relevant pathways that were previously found to be enriched in the latest RLS GWAS meta-analysis. Analysis of our different datasets further supports and highlights the regulatory role of SKOR1, which when dysregulated might represent a key pathogenic element of RLS. A better understanding of SKOR1 and its activity could open new avenues of investigation for the development of a much-needed therapy.

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study (Pearson's correlation coefficient R2 = 0.62). Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10-5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD. FA and CL were funded by the Fonds de Recherche du Québec–Santé. SM is funded by FCT (CEECIND/00684/2017) and by NORTE-01-0145- FEDER-000008, supported by Norte Portugal Regional Programme (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through the European Regional Development Fund (ERDF). FM and LI are funded by Fundaçao de Amparo a Pesquisa do Estado de São Paulo (FAPESP, 2013/07559-3). MLSP and LBJ were funded by Conselho Nacional de Desenvolvimento Científico e Tecnológico, Brazil (CNPq) and by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES). GAR holds a Canada Research Chair in Genetics of the Nervous System and the Wilder Penfield Chair in Neurosciences.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental psychiatric disorder. Genome-wide association studies (GWAS) have identified several loci associated with ADHD. However, understanding the biological relevance of these genetic loci has proven to be difficult. Here, we conduct an ADHD transcriptome-wide association study (TWAS) consisting of 19,099 cases and 34,194 controls and identify 9 transcriptome-wide significant hits, of which 6 genes were not implicated in the original GWAS. We demonstrate that two of the previous GWAS hits can be largely explained by expression regulation. Probabilistic causal fine-mapping of TWAS signals prioritizes KAT2B with a posterior probability of 0.467 in the dorsolateral prefrontal cortex and TMEM161B with a posterior probability of 0.838 in the amygdala. Furthermore, pathway enrichment identifies dopaminergic and norepinephrine pathways, which are highly relevant for ADHD. Overall, our findings highlight the power of TWAS to identify and prioritize putatively causal genes., A recent GWAS reported 12 genetic loci for attention deficit/hyperactivity disorder (ADHD). Here, Liao et al. perform transcriptomic imputation using these data and 12 brain-relevant tissues from GTEx and CMC to identify 9 genes associated with ADHD by TWAS, 3 of which had not yet been reported for ADHD.

Previous studies using whole exome sequencing (WES) have shown that a significant proportion of adult patients with undiagnosed ataxia in European and North American cohorts have a known genetic cause. Little is known about the diagnostic yield of WES in non-Caucasian ataxic populations. Herein, we used WES to investigate a Brazilian cohort of 76 adult patients with idiopathic ataxia previously screened for trinucleotide expansions in known ataxia genes. We collected clinical and radiological data from each patient. WES was performed following standard procedures. Only variants labeled as pathogenic or likely pathogenic according to American college of medical genetics and genomics (ACMG) criteria were retrieved. We determined the diagnostic yield of WES for the whole cohort and also for subgroups defined according to presence or not of pyramidal signs, peripheral neuropathy, and cerebellar atrophy. There were 41 women and 35 men. Mean age at testing was 48 years. Pyramidal signs, peripheral neuropathy, tremor, and cerebellar atrophy were found in 38.1%, 13.1%, 10.5%, and 68.3% of all subjects, respectively. Diagnostic yield of WES was 35.5%. Thirty-six distinct mutations were found in 20 different genes, determining the diagnosis of 18 autosomal recessive and 9 autosomal dominant ataxias. SACS and SPG7 were the most frequently found underlying genes. WES performed better in the subgroup with vs the subgroup without spasticity (p = 0.005). WES was diagnostic in 35.5% of cases of the Brazilian cohort of ataxia cases. These results have implications for diagnosis, genetic counseling and eventually treatment.

Tourette’s Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. To characterize effects of expression quantitative trait loci (eQTLs) in TS and understand biological underpinnings of the disease. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4819 cases and 9488 controls. We demonstrate that increased expression of FLT3 in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further show that there is global dysregulation of FLT3 across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizes FLT3 with a posterior inclusion probability of 0.849. After, we proxy the expression with 100 lymphoblastoid cell lines, and demonstrate that TS cells has a 1.72 increased fold change compared to controls. A phenome-wide association study also points toward FLT3 having links with immune-related pathways such as monocyte count. We further identify several splicing events in MPHOSPH9, CSGALNACT2 and FIP1L1 associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.

Background The genetic and epidemiological features of hereditary ataxias have been reported in several populations; however, Turkey is still unexplored. Due to high consanguinity, recessive ataxias are more common in Turkey than in Western European populations. Objective To identify the prevalence and genetic structure of hereditary ataxias in the Turkish population. Methods Our cohort consisted of 1296 index cases and 324 affected family members. Polymerase chain reaction followed by Sanger sequencing or fragment analysis were performed to screen for the trinucleotide repeat expansions in families with a dominant inheritance pattern, as well as in sporadic cases. The expansion in the frataxin (FXN) gene was tested in all autosomal recessive cases and in sporadic cases with a compatible phenotype. Whole-exome sequencing was applied to 251 probands, selected based on the family history, age of onset, and phenotype. Results Mutations in known ataxia genes were identified in 30% of 1296 probands. Friedreich's ataxia was found to be the most common recessive ataxia in Turkey, followed by autosomal recessive spastic ataxia of Charlevoix-Saguenay. Spinocerebellar ataxia types 2 and 1 were the most common dominant ataxias. Whole-exome sequencing was performed in 251 probands with an approximate diagnostic yield of 50%. Forty-eight novel variants were found in a plethora of genes, suggesting a high heterogeneity. Variants of unknown significance were discussed in light of clinical data. Conclusion With the large sample size recruited across the country, we consider that our results provide an accurate picture of the frequency of hereditary ataxias in Turkey. (c) 2021 International Parkinson and Movement Disorder Society, Suna and Inan Kirac Foundation; Koc UniversityKoc University; Bogazici UniversityBogazici University, This work was supported by funds from Suna and Inan Kirac Foundation, Koc University, Bogazici University.

Hereditary spastic paraplegia is a group of rare motor neuron diseases considered to be inherited in a classical monogenic Mendelian manner. Although the typical inheritance of spastic paraplegia type 7 is autosomal recessive, several reports have suggested that SPG7 variants may also cause autosomal dominant HSP. We aimed to conduct an exome-wide genetic analysis on a large Canadian cohort of hereditary spastic paraplegia patients and controls to examine the association of SPG7 and hereditary spastic paraplegia. In total, 585 hereditary spastic paraplegia patients from 372 families and 1,175 controls, including 580 unrelated individuals, were analyzed for the presence of SPG7 variants. Whole exome sequencing was performed on 400 hereditary spastic paraplegia patients (291 index cases) and all 1,175 controls. After excluding 38 biallelic hereditary spastic paraplegia type 7 patients, the frequency of heterozygous pathogenic/likely pathogenic SPG7 variant carriers (4.8%) among hereditary spastic paraplegia unrelated index cases who underwent WES, was significantly higher than among unrelated controls (1.7%; OR=2.88, 95%CI=1.24-6.66, p=0.009). The heterozygous SPG7 p.(Ala510Val) variant was found in 3.7% of index cases vs. 0.85% in unrelated controls (OR=4.42, 95%CI=1.49-13.07, p=0.005). We identified four heterozygous SPG7 variant carriers with an additional pathogenic variant in genes known to cause hereditary spastic paraplegia, compared to zero in controls (OR=19.58, 95%CI=1.05-365.13, p=0.0031; Fisher’s Exact test with Haldane-Anscombe correction), indicating potential digenic inheritance. We further identified four families with heterozygous variants in SPG7 and SPG7-interacting genes (CACNA1A, AFG3L2 and MORC2). Out of these, there is especially compelling evidence for epistasis between SPG7 and AFG3L2. The p.(Ile705Thr) variant in AFG3L2 is located at the interface between hexamer subunits, in a hotspot of mutations associated with spinocerebellar ataxia type 28 that affect its proteolytic function. Our results provide evidence for complex inheritance in SPG7-associated hereditary spastic paraplegia, which may include recessive and possibly dominant and digenic/epistasis forms of inheritance.

Olgun, Gulden/0000-0002-4467-1610; Sahin, Erdi/0000-0002-5792-2888; Tastan, Oznur/0000-0001-7058-5372; Akcimen, Fulya/0000-0003-0931-5247; Kartal, Ece/0000-0002-7720-455X WOS:000542467300001 PubMed ID: 32579787 The last decade has proven that amyotrophic lateral sclerosis (ALS) is clinically and genetically heterogeneous, and that the genetic component in sporadic cases might be stronger than expected. This study investigates 1,200 patients to revisit ALS in the ethnically heterogeneous yet inbred Turkish population. Familial ALS (fALS) accounts for 20% of our cases. The rates of consanguinity are 30% in fALS and 23% in sporadic ALS (sALS). Major ALS genes explained the disease cause in only 35% of fALS, as compared with similar to 70% in Europe and North America. Whole exome sequencing resulted in a discovery rate of 42% (53/127). Whole genome analyses in 623 sALS cases and 142 population controls, sequenced within Project MinE, revealed well-established fALS gene variants, solidifying the concept of incomplete penetrance in ALS. Genome-wide association studies (GWAS) with whole genome sequencing data did not indicate a new risk locus. Coupling GWAS with a coexpression network of disease-associated candidates, points to a significant enrichment for cell cycle- and division-related genes. Within this network, literature text-mining highlightsDECR1, ATL1, HDAC2, GEMIN4, andHNRNPA3as important genes. Finally, information on ALS-related gene variants in the Turkish cohort sequenced within Project MinE was compiled in the GeNDAL variant browser (www.gendal.org). TUBITAKTurkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [109S075]; Bogazici University Research FundsBogazici University [15B01P1]; Suna and Inan Kirac Foundation [2005-2020] TUBITAK, Grant/Award Number: 109S075; Bogazici University Research Funds, Grant/Award Number: 15B01P1; Suna and Inan Kirac Foundation, Grant/Award Number: 2005-2020

Spinocerebellar ataxia types 1, 2, 3 and Huntington disease are neurodegenerative disorders caused by expanded CAG repeats.We performed an in-silico analysis of CAG repeats in ATXN1, ATXN2, ATXN3, and HTT using 30× whole-=genome sequencing data of 2504 samples from the 1000 Genomes Project.Seven HTT-positive, 3 ATXN2-positive, 1 ATXN3-positive, and 6 possibly ATXN1-positive samples were identified. No correlation was found between the repeat sizes of the different genes. The distribution of CAG alleles varied by ethnicity.Our results suggest that there may be asymptomatic small expanded repeats in almost 0.5% of these populations. © 2020 International Parkinson and Movement Disorder Society.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease leading to motor neuron damage. In this study, the clinical, demographic, and genetic features of ALS patients in the city of Sakarya, Turkey, were investigated. Patients with an established diagnosis of ALS according to the Awaji criteria were included. Age, sex, age at onset of ALS, initial complaints, consanguineous marriage, and genetic features were retrospectively investigated. Conventional genetic analysis and NGS were used for molecular evaluation of patients. A total of 55 probands (10 familial, 45 sporadic) in whom ALS was suspected due to their phenotypic features were included. Thirty-two patients were male (58.2%), and 23 were female (41.8%); their mean ages were 62.65 +/- 13 years. The mean age of onset for 37 familial patients from 10 families was 49.9 years. Two cases had juvenile-onset. Fourteen (25.5%) bulbar-onset versus 40 (72.7%) limb-onset patients were detected; one patient had both. Six (10.9%) patients showed marked frontotemporal dementia. Twenty-nine (52.7%) patients died during the follow-up period. Genetic analysis identified causative variants in eleven cases, carrying variants in six different ALS genes (C9orf72,SOD1,VCP,SPG11,TBK1, and SH3TC2). Genetic investigations have revealed more than 40 genes to be involved in the pathogenesis of ALS. Our relatively small study cohort restricted to one province of Turkey, however, prone to migration, consists of 10/55 familial ALS cases, which harbor two rare (SH3TC2-p.Met523Thr and TBK1-p.Glu643del) and two novel (SPG11-p.Lys656Valfs*11 and VCP-p.Arg191Pro) mutations contributing to the literature. Suna and Inan Kirac Foundation at Koc University-KUTTAM The genetic analyses of this study were financed by Suna and Inan Kirac Foundation at Koc University-KUTTAM. WOS:000548764100001 32671691 Q3

Machado-Joseph disease (MJD/SCA3) is the most common form of dominantly inherited ataxia worldwide. The disorder is caused by an expanded CAG repeat in the ATXN3 gene. Past studies have revealed that the length of the expansion partly explains the disease age at onset (AO) variability of MJD, which is confirmed in this study. Using a total of 786 MJD patients from five different geographical origins, a genome-wide association study (GWAS) was conducted to identify additional AO modifying factors that could explain some of the residual AO variability. We identified nine suggestively associated loci (P < 1 × 10−5). These loci were enriched for genes involved in vesicle transport, olfactory signaling, and synaptic pathways. Furthermore, associations between AO and the TRIM29 and RAG genes suggests that DNA repair mechanisms might be implicated in MJD pathogenesis. Our study demonstrates the existence of several additional genetic factors, along with CAG expansion, that may lead to a better understanding of the genotype-phenotype correlation in MJD.

Objective: After the initial report of a CHCHD10 mutation in mitochondrial disease with features resembling amyotrophic lateral sclerosis (ALS), CHCHD10 mutations have been considered to be a frequent cause for ALS. However, the exact pathogenicity and clinical significance of these mutations remain unclear. Here, we aimed to determine the role of CHCHD10 mutations in ALS. Methods: We analyzed 4,365 whole genome sequenced ALS patients and 1,832 controls from 7 different countries and examined all nonsynonymous single nucleotide variants in CHCHD10. These were tested for association with ALS, independently and in aggregate using several genetic burden tests (including sequence kernel association test [SKAT], optimal unified test [SKAT-O], and Firth logistic regression). Results: We identified 3 new variants in cases, but only 1 was ALS-specific. lso, 1 control-specific mutation was identified. There was no increased burden of rare coding mutations among ALS patients compared to controls (p=0.86, p=0.86, and p=0.88 for SKAT, SKAT-O, and Firth, respectively). The few carriers with potential pathogenic CHCHD10 mutations exhibited a slowly progressive ALS-like phenotype with atypical features such as myopathy and deafness. Interpretation: CHCHD10 mutations seem to be a far less prevalent cause of pure ALS than previously suggested, and instead appear related to more complex phenotypes. There appears to be insufficient evidence for the pathogenicity of most previously reported variants in pure ALS. This study shows that routine testing for CHCHD10 mutations in pure ALS is not recommended and illustrates the importance of sufficient genetic and functional evidence in establishing pathogenicity of genetic variants.

Currently, a total of 19 genetic loci are associated with the risk for developing RLS. This study aimed to assess these RLS predisposing genetic variants, as well as investigate the epidemiological profile and diagnostic features of individuals with RLS in the Québec population, using an interviewer–administered questionnaire. A total of 18 RLS-associated variants were genotyped in the Québec population-based CARTaGENE cohort. A case–control series consisting of 1,362 RLS cases and 1,379 age-matched unaffected controls was used to conduct a genetic and epidemiological association study that integrated the first four RLS diagnostic features of affected individuals, as well as additional RLS-related questions (e.g. frequency of the symptoms and number of total pregnancies in female). Five RLS-predisposing variants were significantly associated after Bonferroni correction and an additional five variants were nominally associated with RLS (p < 0.05). BTBD9 was the strongest genetic risk factor in our cohort (rs9296249, OR = 1.71, p = 9.57 × 10−10). The patient group that met all four essential diagnostic criteria of RLS provided the most significant genetic findings. These results suggest that employing the questionnaire which included standard diagnostic criteria of RLS could improve the accuracy of the survey-based studies.

Tourette’s Syndrome (TS) is a neurodevelopmental disorder that is characterized by motor and phonic tics. A recent TS genome-wide association study (GWAS) identified a genome-wide significant locus. However, determining the biological mechanism of GWAS signals remains difficult. Here, we conduct a TS transcriptome-wide association study (TWAS) consisting of 4,819 cases and 9,488 controls and found that increased expression ofFLT3in the dorsolateral prefrontal cortex (DLPFC) is associated with TS. We further showed that there is global dysregulation ofFLT3across several brain regions and probabilistic causal fine-mapping of the TWAS signal prioritizesFLT3with a posterior inclusion probability of 0.849. We validated the gene’s expression in 100 lymphoblastoid cell lines, establishing that TS cells had a 1.72 increased fold change compared to controls. A phenome-wide association study points towardsFLT3having links with immune-related pathways such as monocyte count. We also identify several splicing events inMPHOSPH9, CSGALNACT2andFIP1L1associated with TS, which are also implicated in immune function. This analysis of expression and splicing begins to explore the biology of TS GWAS signals.

IntroductionSjogren-Larsson syndrome (SLS) is a rare congenital disorder characterized by the triad of ichthyosis, spasticity, and mental retardation. Patients are usually referred to dermatology clinics during infancy. As paraplegia becomes the most debilitating symptom of the disease within a few years, ichthyosis, although a major burden for the patient, takes a back seat. Optimum treatment of ichthyosis in these children and the effect of treatment on different aspects such as severity of the ichthyosis, pruritus, or quality of life of the patients' and their caregivers is not well established. Materials and Methods: Genetic background of eight patients from three families diagnosed clinically with SLS was determined with whole-exome and Sanger sequencing. Clinical phenotypes, laboratory findings, magnetic resonance imaging (MRI), and treatment of the ichthyosis with acitretin were assessed. Results: All patients had the classical triad of Sjogren-Larsson syndrome. Genetic analysis revealed that one patient had a novel c.799-1 (+/+) homozygous splicing mutation in the ALDH3A2 gene. Other patients had the c.683G>A p.R228H (NM_000382.2) mutation in the same gene. Other manifestations included skeletal anomalies, enamel hypoplasia, bilateral T2-hyperintensities in white matter, and moderate-severe pruritus. Acitretin treatment in a maintenance dose of 0.25mg/kg/day decreased the severity of ichthyosis in all children. It increased quality of life significantly in all of the children and their caregivers. Conclusion: We conclude that ichthyosis can be treated effectively with low-dose acitretin in children with Sjogren-Larsson syndrome, and this treatment is associated with a significant improvement in the quality of life.

WOS:000431829000017 PubMed: 29453415 Amyotrophic lateral sclerosis (ALS) is a late-onset motor neuron disease with mostly dominant inheritance and a life expectancy of 2-5 years; however, a quite common occurrence of atypical forms of the disease, due to recessive inheritance, has become evident with the use of NGS technologies. In this paper, we describe a family with close consanguinity for at least four generations, suffering from a slowly progressive form of ALS. Spastic walking is observed since teenage years, while bulbar symptoms start much later, at the fifth or sixth decade of life. Patients usually die because of respiratory failure. Using whole-exome sequencing, we identified a novel homozygous p.(Val94Ala) (c.281T>C) (NG_052910.1) (NM_006459) variation in the endoplasmic reticulum lipid raft associated protein 1 (ERLIN1) gene, which segregates with the disease in the family. Here we suggest that ERLIN1 variants, previously shown in juvenile hereditary spastic paraplegia cases, may also be the cause of a slowly progressive early-onset ALS, starting with upper motor neuron features and developing into classical ALS with the addition of lower motor neuron dysfunction. We also demonstrate that ATP-binding cassette subfamily C member 2 (ABCC2) gene, responsible for hyperbilirubinemia, is linked to ERLIN1.

Background Amyotrophic lateral sclerosis (ALS) is a devastating disease whose complex pathology has been associated with a strong genetic component in the context of both familial and sporadic disease. Herein, we adopted a next-generation sequencing approach to Greek patients suffering from sporadic ALS (together with their healthy counterparts) in order to explore further the genetic basis of sporadic ALS (sALS). Results Whole-genome sequencing analysis of Greek sALS patients revealed a positive association between FTO and TBC1D1 gene variants and sALS. Further, linkage disequilibrium analyses were suggestive of a specific disease-associated haplotype for FTO gene variants. Genotyping for these variants was performed in Greek, Sardinian, and Turkish sALS patients. A lack of association between FTO and TBC1D1 variants and sALS in patients of Sardinian and Turkish descent may suggest a founder effect in the Greek population. FTO was found to be highly expressed in motor neurons, while in silico analyses predicted an impact on FTO and TBC1D1 mRNA splicing for the genomic variants in question. Conclusions To our knowledge, this is the first study to present a possible association between FTO gene variants and the genetic etiology of sALS. In addition, the next-generation sequencing-based genomics approach coupled with the two-step validation strategy described herein has the potential to be applied to other types of human complex genetic disorders in order to identify variants of clinical significance. Electronic supplementary material The online version of this article (10.1186/s40246-017-0126-2) contains supplementary material, which is available to authorized users.

Restless legs syndrome is a common complex disorder with different genetic and environmental risk factors. Here we used human cell lines to conduct an RNA-Seq study and observed how the gene showing the most significant association with RLS, MEIS1, acts as a regulator of the expression of many other genes. Some of the genes affected by its expression level are linked to pathways previously reported to be associated with RLS. We found that in cells where MEIS1 expression was either increased or prevented, mineral absorption is the principal dysregulated pathway. The mineral absorption pathway genes, HMOX1 and VDR are involved in iron metabolism and response to vitamin D, respectively. This shows a strong functional link to the known RLS pathways. We observed the same enrichment of the mineral absorption pathway in postmortem brain tissues of RLS patients showing a reduced expression of MEIS1. The expression of genes encoding metallothioneins (MTs) was observed to be dysregulated across the RNA-Seq datasets generated from both human cells and tissues. MTs are highly relevant to RLS as they bind intracellular metals, protect against oxidative stress and interact with ferritins which manage iron level in the central nervous system. Overall, our study suggests that in a subset of RLS patients, the contribution of MEIS1 appears to be associated to its downstream regulation of genes that are more directly involved in pathways that are relevant to RLS. While MTs have been implicated in the pathogenesis of neurodegenerative diseases such as Parkinson's diseases, this is a first report to propose that they have a role in RLS.

A homozygous pentanucleotide expansion in the RFC1 gene has been shown to be a common cause of late-onset ataxia. In the general population a total of four different repeat conformations have been observed: a wild type sequence AAAAG (11 repeats), and longer expansions of AAAAG, AAAGG and AAGGG sequences. However, in ataxia cases only the AAGGG expansion has been shown to be pathogenic. In this study, we assessed the prevalence and nature of RFC1 repeat expansions in three adult-onset ataxia cohorts: Brazilian (n = 23) and Canadian (n = 26) cases that tested negative for other known ataxia mutations, as well as a cohort of randomly selected Canadian cases (n = 128) without regard to a genetic diagnosis. We identified the homozygous AAGGG pathogenic expansion in only one Brazilian family with two affected siblings, and in one Canadian case. The RFC1 expansion may therefore not be a common cause of adult-onset ataxia in these populations. Interestingly we observed two new repeat motifs, AAGAG and AGAGG, which indicates the dynamic nature of the pentanucleotide expansion sequence. To assess the frequency of these two new repeat conformations in the general population we screened 163 healthy individuals. These novel motifs were more frequent in patients versus controls. While we cannot be certain that the homozygous genotypes of the novel expanded conformations are pathogenic, their occurrence should nonetheless be taken into consideration in future studies.

The genetic factors predisposing to essential tremor (ET), of one of the most common movement disorders, remains largely unknown. While current studies have examined the contribution of both common and rare genetic variants, very few have investigated the ET transcriptome. To understand pathways and genes relevant to ET, we used an RNA sequencing approach to interrogate the transcriptome of two cerebellar regions, the dentate nucleus and cerebellar cortex, in 16 cases and 16 age- and sex-matched controls. Additionally, a phenome-wide association study (pheWAS) of the dysregulated genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. We identified several novel dysregulated genes includingCACNA1A, a calcium voltage-gated channel implicated in ataxia. Furthermore, several pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. A subsequent examination of the ET GWGAS data (N=7,154) also flagged genes involved in calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. Interestingly, the pheWAS identified that the dysregulated gene,SHF, is associated with a blood pressure medication (P=9.3E-08), which is commonly used to reduce tremor in ET patients. Lastly, it is also notable that the dentate nucleus and cerebellar cortex have different transcriptomes, suggesting that different regions of the cerebellum have spatially different transcriptomes.

Essential tremor (ET) is a common movement disorder that has a high heritability. A number of genetic studies have associated different genes and loci with ET, but few have investigated the biology of any of these genes.STK32Bwas significantly associated with ET in a large GWAS study and was found to be overexpressed in ET cerebellar tissue. Here, we overexpressedSTK32Bin human cerebellar DAOY cells and used an RNA-Seq approach to identify differentially expressed genes by comparing the transcriptome profile of these cells to the one of control DAOY cells. Pathway and gene ontology enrichment identified axon guidance, olfactory signalling and calcium-voltage channels as significant. Additionally, we show that overexpressingSTK32Baffects transcript levels of previously implicated ET genes such asFUS. Our results investigate the effects of overexpressedSTK32Band suggest that it may be involved in relevant ET pathways and genes.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive fatal neurodegenerative disease affecting 1 in 350 people. The aim of Project MinE is to elucidate the pathophysiology of ALS through whole-genome sequencing at least 15,000 ALS patients and 7,500 controls at 30X coverage. Here, we present the Project MinE data browser (databrowser.projectmine.com). a unique and intuitive one-stop, open-access server that provides detailed information on genetic variation analyzed in a new and still growing set of 4,366 ALS cases and 1,832 matched controls. Through its visual components and interactive design, the browser specifically aims to be a resource to those without a biostatistics background and allow clinicians and preclinical researchers to integrate Project MinE data into their own research. The browser allows users to query a transcript and immediately access a unique combination of detailed (meta)data, annotations and association statistics that would otherwise require analytic expertise and visits to scattered resources.

Mirror movements are unintended movements occurring on one side of the body that mirror the contralateral voluntary ones. It has been proposed that mirror movements occur due to abnormal decussation of the corticospinal pathways. Using detailed multidisciplinary approach, we aimed to enlighten the detailed mechanism underlying the mirror movements in a case subject who is diagnosed with mirror movements of the hands and we compared the findings with the unaffected control subjects. To evaluate the characteristics of mirror movements, we used several techniques including whole exome sequencing, computed tomography, diffusion tensor imaging and transcranial magnetic stimulation. Computed tomography showed the absence of a spinous process of C5, fusion of the body of C5-C6 vertebrae, hypoplastic dens and platybasia of the posterior cranial fossa. A syrinx cavity was present between levels C3-C4 of the spinal cord. Diffusion tensor imaging of the corticospinal fibers showed disorganization and minimal decussations at the lower medulla oblongata. Transcranial magnetic stimulation showed that motor commands were distributed to the motor neuron pools on the left and right sides of the spinal cord via fast-conducting corticospinal tract fibers. Moreover, a heterozygous missense variation in the deleted in colorectal carcinoma gene has been observed. Developmental absence of the axonal guidance molecules or their receptors may result in abnormalities in the leading of the corticospinal fibers. Clinical evaluations and basic neuroscience techniques, in this case, provide information for this rare disease and contribute to our understanding of the normal physiology of bimanual coordination. We would like to thank our index patient and control subjects for their participation. Also, we acknowledge the role of Koç University, Bilkent University as well as Suna and İnan Kıraç Foundation for funding this study.

Objective: Identification of causative mutations in 3 consanguineous families (with 4 affected members) referred to our center with young-onset motor neuron disease and overlapping phenotypes resembling autosomal recessive juvenile amyotrophic lateral sclerosis (ARJALS) and autosomal recessive hereditary spastic paraplegia (ARHSP). Methods: Patients have a slowly progressive motor neuron disease with upper and lower motor neuron dysfunction. There is distal muscle weakness and atrophy associated with pyramidal signs. Whole-exome sequencing was performed on the patients and the unaffected parent samples to identify disease-causing mutations. Variants were prioritized according to their predicted pathogenicity and their relevance to the clinical phenotypes. Results: Five distinct homozygous mutations within the SPG11 gene were identified, 3 of which were novel and truncating: c.7155T>G/p.Tyr2385Ter, c.2250delT/p.Phe750Leufs*3, and c.1966_1967delAA/p.Lys656Valfs*11. The copresence of 2 distinct homozygous missense variations was observed in 2 families: c.6224A>G/p.Asn2075Ser and c.7132T>C/p.Phe2378Leu. The segregation of these variations in the family members was validated by Sanger sequencing. Conclusions: Four patients with juvenile-onset motor neuron disease with consanguineous parents were found to carry homozygous mutations in the SPG11 gene. Our findings confirm the overlapping phenotypes of SPG11 -based ARJALS and ARHSP, indicating that these 2 entities may be the extreme phenotypes of the same disease continuum with many common features. This, in turn, confirms the difficult differential diagnosis of these 2 diseases in the clinic.