Spinal cord extracts of amyotrophic lateral sclerosis spread TDP-43 pathology in cerebral organoids.

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder caused by progressive loss of motor neurons and there is currently no effective therapy. Cytoplasmic mislocalization and aggregation of TAR DNA-binding protein 43 kDa (TDP-43) within the CNS is a pathological hallmark in sporadic ALS and prion-like propagation of pathogenic TDP-43 is thought to be implicated in disease progression. However, cell-to-cell transmission of pathogenic TDP-43 in the human CNS has not been confirmed experimentally. Here we used induced pluripotent stem cells (iPSCs)-derived cerebral organoids as recipient CNS tissue model that are anatomically relevant human brain. We injected postmortem spinal cord protein extracts individually from three non-ALS or five sporadic ALS patients containing pathogenic TDP-43 into the cerebral organoids to validate the templated propagation and spreading of TDP-43 pathology in human CNS tissue. We first demonstrated that the administration of spinal cord extracts from an ALS patient induced the formation of TDP-43 pathology that progressively spread in a time-dependent manner in cerebral organoids, suggesting that pathogenic TDP-43 from ALS functioned as seeds and propagated cell-to-cell to form de novo TDP-43 pathology. We also reported that the administration of ALS patient-derived protein extracts caused astrocyte proliferation to form astrogliosis in cerebral organoids, reproducing the pathological feature seen in ALS. Moreover, we showed pathogenic TDP-43 induced cellular apoptosis and that TDP-43 pathology correlated with genomic damage due to DNA double-strand breaks. Thus, our results provide evidence that patient-derived pathogenic TDP-43 can mimic the prion-like propagation of TDP-43 pathology in human CNS tissue. Our findings indicate that our assays with human cerebral organoids that replicate ALS pathophysiology have a promising strategy for creating readouts that could be used in future drug discovery efforts against ALS.

Rare-variant and polygenic analyses of amyotrophic lateral sclerosis in the French-Canadian genome.

PURPOSE: The genetic etiology of amyotrophic lateral sclerosis (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. METHODS: 335 ALS cases and 356 controls from Québec, Canada were concurrently tested by microarray genotyping and targeted sequencing of ALS genes known at the time of study inception. ALS genome-wide association studies summary statistics were used to estimate an ALS polygenic risk score (PRS). Cases and controls were subdivided into rare-variant heterozygotes and non-heterozygotes. RESULTS: Risk for ALS was significantly associated with PRS and rare variants independently in a logistic regression model. Although ALS PRS predicted a small amount of ALS risk overall, the effect was most pronounced between ALS cases and controls that were not heterozygous for a rare variant in the ALS genes surveyed. CONCLUSION: Both PRS and rare variants in ALS genes impact risk for ALS. PRS for ALS is most informative when rare variants are not observed in ALS genes.

Evolution of a Human-Specific Tandem Repeat Associated with ALS.

Tandem repeats are proposed to contribute to human-specific traits, and more than 40 tandem repeat expansions are known to cause neurological disease. Here, we characterize a human-specific 69 bp variable number tandem repeat (VNTR) in the last intron of WDR7, which exhibits striking variability in both copy number and nucleotide composition, as revealed by long-read sequencing. In addition, greater repeat copy number is significantly enriched in three independent cohorts of individuals with sporadic amyotrophic lateral sclerosis (ALS). Each unit of the repeat forms a stem-loop structure with the potential to produce microRNAs, and the repeat RNA can aggregate when expressed in cells. We leveraged its remarkable sequence variability to align the repeat in 288 samples and uncover its mechanism of expansion. We found that the repeat expands in the 3'-5' direction, in groups of repeat units divisible by two. The expansion patterns we observed were consistent with duplication events, and a replication error called template switching. We also observed that the VNTR is expanded in both Denisovan and Neanderthal genomes but is fixed at one copy or fewer in non-human primates. Evaluating the repeat in 1000 Genomes Project samples reveals that some repeat segments are solely present or absent in certain geographic populations. The large size of the repeat unit in this VNTR, along with our multiplexed sequencing strategy, provides an unprecedented opportunity to study mechanisms of repeat expansion, and a framework for evaluating the roles of VNTRs in human evolution and disease.

Moyamoya Disease Susceptibility Gene RNF213 Regulates Endothelial Barrier Function.

BACKGROUND: Variants in the ring finger protein 213 (RNF213) gene are known to be associated with increased predisposition to cerebrovascular diseases development. Genomic studies have identified RNF213 as a major risk factor of Moyamoya disease in East Asian descendants. However, little is known about the RNF213 (ring finger protein 213) biological functions or its associated pathogenic mechanisms underlying Moyamoya disease. METHODS: To investigate RNF213 loss-of-function effect in endothelial cell, stable RNF213-deficient human cerebral endothelial cells were generated using the CRISPR-Cas9 genome editing technology. RESULTS: In vitro assays, using RNF213 knockout brain endothelial cells, showed clear morphological changes and increased blood-brain barrier permeability. Downregulation and delocalization of essential interendothelial junction proteins involved in the blood-brain barrier maintenance, such as PECAM-1 (platelet endothelial cell adhesion molecule-1), was also observed. Brain endothelial RNF213-deficient cells also showed an abnormal potential to transmigration of leukocytes and secreted high amounts of proinflammatory cytokines. CONCLUSIONS: Taken together, these results indicate that RNF213 could be a key regulator of cerebral endothelium integrity, whose disruption could be an early pathological mechanism leading to Moyamoya disease. This study also further reinforces the importance of blood-brain barrier integrity in the development of Moyamoya disease and other RNF213-associated diseases.

Investigation of the causal relationship between ALS and autoimmune disorders: a Mendelian randomization study.

BACKGROUND: Epidemiological studies have reported an association between amyotrophic lateral sclerosis (ALS) and different autoimmune disorders. This study aims to explore the causal relationship between autoimmune disorders and ALS using Mendelian randomization (MR). METHODS: To test the genetically predicted effects of liability towards immune-related outcomes on ALS risk, we used summary statistics from the largest European genome-wide association studies (GWAS) for these disorders in a two-sample MR setting. To do this, we extracted single nucleotide polymorphisms (SNPs) from the GWAS, which strongly associated with the 12 traits, and queried their effects in a large European ALS GWAS (27,265 cases and 110,881 controls). To avoid bias in our MR instruments related to the complex linkage disequilibrium structure of the human leukocyte antigen (HLA) region, we excluded SNPs within this region from the analyses. We computed inverse-variance weighted (IVW) MR estimates and undertook sensitivity analyses using MR methods robust to horizontal pleiotropy. We also performed a reverse MR analysis testing the causal effects of ALS on the above autoimmune traits. RESULTS: After applying Bonferroni correction for multiple testing, our MR analyses showed that the liability to autoimmune disorders does not affect ALS risk. Our reverse MR analysis also did not support the effects of liability to ALS on other autoimmune disorders. The results of the main IVW MR analyses were generally supported by our sensitivity MR analyses. The variance in the exposures explained by the sets of SNPs used as MR instruments ranged from 8.1 × 10-4 to 0.31. Our MR study was well-powered to detect effects as small as an odds ratio (OR) of 1.045 for ALS in the main MR and as small as an OR of 1.32 in the reverse MR. CONCLUSION: Our MR study does not support a relationship between liability to autoimmune disorders and ALS risk in the European population. The associations observed in epidemiological studies could be partly attributed to shared biology or environmental confounders.

Diagnostic Yield of Whole Exome Sequencing for Adults with Ataxia: a Brazilian Perspective.

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.

Genetic architecture and adaptations of Nunavik Inuit.

The Canadian Inuit have a distinct population background that may entail particular implications for the health of its individuals. However, the number of genetic studies examining this Inuit population is limited, and much remains to be discovered in regard to its genetic characteristics. In this study, we generated whole-exome sequences and genomewide genotypes for 170 Nunavik Inuit, a small and isolated founder population of Canadian Arctic indigenous people. Our study revealed the genetic background of Nunavik Inuit to be distinct from any known present-day population. The majority of Nunavik Inuit show little evidence of gene flow from European or present-day Native American peoples, and Inuit living around Hudson Bay are genetically distinct from those around Ungava Bay. We also inferred that Nunavik Inuit have a small effective population size of 3,000 and likely split from Greenlandic Inuit ∼10.5 kya. Nunavik Inuit went through a bottleneck at approximately the same time and might have admixed with a population related to the Paleo-Eskimos. Our study highlights population-specific genomic signatures in coding regions that show adaptations unique to Nunavik Inuit, particularly in pathways involving fatty acid metabolism and cellular adhesion (CPNE7, ICAM5, STAT2, and RAF1). Subsequent analyses in selection footprints and the risk of intracranial aneurysms (IAs) in Nunavik Inuit revealed an exonic variant under weak negative selection to be significantly associated with IA (rs77470587; P = 4.6 × 10-8).

Expanded CAG Repeats in ATXN1, ATXN2, ATXN3, and HTT in the 1000 Genomes Project.

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.

Evidence for Non-Mendelian Inheritance in Spastic Paraplegia 7.

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.

Missense variants in ATP1A3 and FXYD gene family are associated with childhood-onset schizophrenia.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia defined as onset before age of 13. Here we report on two unrelated cases diagnosed with both COS and alternating hemiplegia of childhood (AHC), and for whom two distinct pathogenic de novo variants were identified in the ATP1A3 gene. ATP1A3 encodes the α-subunit of a neuron-specific ATP-dependent transmembrane sodium-potassium pump. Using whole exome sequencing data derived from a cohort of 17 unrelated COS cases, we also examined ATP1A3 and all of its interactors known to be expressed in the brain to establish if variants could be identified. This led to the identification of a third case with a possibly damaging missense mutation in ATP1A3 and three others cases with predicted pathogenic missense variants in the FXYD gene family (FXYD1, FXYD6, and FXYD6-FXYD2 readthrough). FXYD genes encode proteins that modulate the ATP-dependant pump function. This report is the first to identify variants in the same pathway for COS. Our COS study illustrates the interest of stratifying a complex condition according to the age of onset for the identification of deleterious variants. Whereas ATP1A3 is a replicated gene in rare neuropediatric diseases, this gene has previously been linked with COS in only one case report. The association with rare variants in FXYD gene family is novel and highlights the interest of exploring these genes in COS as well as in pediatric neurodevelopmental disorders.

Oligogenicity, C9orf72 expansion, and variant severity in ALS.

"Oligogenic inheritance" is used to describe cases where more than one rare pathogenic variant is observed in the same individual. While multiple variants can alter disease presentation, the necessity of multiple variants to instigate pathogenesis has not been addressed in amyotrophic lateral sclerosis (ALS). We sequenced ALS-associated genes in C9orf72-expansion-positive and negative ALS patients, alongside unaffected controls, to test the importance of oligogenicity and variant deleteriousness in ALS. We found that all groups had similar numbers of rare variants, but that variant severity was significantly higher in C9orf72-negative ALS cases, suggesting sufficiency of C9orf72 expansion to cause ALS alone.

Multiomics Analyses Identify Genes and Pathways Relevant to Essential Tremor.

INTRODUCTION: The genetic factors and molecular mechanisms predisposing to essential tremor (ET) remains largely unknown. OBJECTIVE: The objective of this study was to identify pathways and genes relevant to ET by integrating multiomics approaches. METHODS: Case-control RNA sequencing of 2 cerebellar regions was done for 64 samples. A phenome-wide association study (pheWAS) of the differentially expressed genes was conducted, and a genome-wide gene association study (GWGAS) was done to identify pathways overlapping with the transcriptomic data. Finally, a transcriptome-wide association study (TWAS) was done to identify novel risk genes for ET. RESULTS: We identified several novel dysregulated genes, including CACNA1A and SHF. Pathways including axon guidance, olfactory loss, and calcium channel activity were significantly enriched. The ET GWGAS data found calcium ion-regulated exocytosis of neurotransmitters to be significantly enriched. The TWAS also found calcium and olfactory pathways enriched. The pheWAS identified that the underexpressed differentially expressed gene, SHF, is associated with a blood pressure medication (P = 9.3E-08), which is used to reduce tremor in ET patients. Treatment of cerebellar DAOY cells with the ET drug propranolol identified increases in SHF when treated, suggesting it may rescue the underexpression. CONCLUSION: We found that calcium-related pathways were enriched across the GWGAS, TWAS, and transcriptome. SHF was shown to have significantly decreased expression, and the pheWAS showed it was associated with blood pressure medication. The treatment of cells with propranolol showed that the drug restored levels of SHF. Overall, our findings highlight the power of integrating multiple different approaches to prioritize ET pathways and genes. © 2020 International Parkinson and Movement Disorder Society.

Mutations in ATP13A2 (PARK9) are associated with an amyotrophic lateral sclerosis-like phenotype, implicating this locus in further phenotypic expansion.

BACKGROUND: Amyotrophic lateral sclerosis [1] is a genetically heterogeneous neurodegenerative disorder, characterized by late-onset degeneration of motor neurons leading to progressive limb and bulbar weakness, as well as of the respiratory muscles, which is the primary cause of disease fatality. To date, over 25 genes have been implicated as causative in ALS with C9orf72, SOD1, FUS, and TARDBP accounting for the majority of genetically positive cases. RESULTS: We identified two patients of Italian and French ancestry with a clinical diagnosis of juvenile-onset ALS who were mutation-negative in any of the known ALS causative genes. Starting with the index case, a consanguineous family of Italian origin, we performed whole-exome sequencing and identified candidate pathogenic mutations in 35 genes, 27 of which were homozygous. We next parsed all candidates against a cohort of 3641 ALS cases; only ATP13A2 was found to harbor recessive changes, in a patient with juvenile-onset ALS, similar to the index case. In vivo complementation of ATP13A2 using a zebrafish surrogate model that focused on the assessment of motor neuron morphology and cerebellar integrity confirmed the role of this gene in central and peripheral nervous system maintenance and corroborated the damaging direction of effect of the change detected in the index case of this study. CONCLUSIONS: We here expand the phenotypic spectrum associated with genetic variants in ATP13A2 that previously comprised Kufor-Rakeb syndrome, spastic paraplegia 78, and neuronal ceroid lipofuscinosis type 12 (CLN12), to also include juvenile-onset ALS, as supported by both genetic and functional data. Our findings highlight the importance of establishing a complete genetic profile towards obtaining an accurate clinical diagnosis.

RNF213 Is Associated with Intracranial Aneurysms in the French-Canadian Population.

Intracranial aneurysms (IAs) are the result of focal weakness in the artery wall and have a complex genetic makeup. To date, genome-wide association and sequencing studies have had limited success in identifying IA risk factors. Distinct populations, such as the French-Canadian (FC) population, have increased IA prevalence. In our study, we used exome sequencing to prioritize risk variants in a discovery cohort of six FC families affected by IA, and the analysis revealed an increased variation burden for ring finger protein 213 (RNF213). We resequenced RNF213 in a larger FC validation cohort, and association tests on further identified variants supported our findings (SKAT-O, p = 0.006). RNF213 belongs to the AAA+ protein family, and two variants (p.Arg2438Cys and p.Ala2826Thr) unique to affected FC individuals were found to have increased ATPase activity, which could lead to increased risk of IA by elevating angiogenic activities. Common SNPs in RNF213 were also extracted from the NeuroX SNP-chip genotype data, comprising 257 FC IA-affected and 1,988 control individuals. We discovered that the non-ancestral allele of rs6565666 was significantly associated with the affected individuals (p = 0.03), and it appeared as though the frequency of the risk allele had changed through genetic drift. Although RNF213 is a risk factor for moyamoya disease in East Asians, we demonstrated that it might also be a risk factor for IA in the FC population. It therefore appears that the function of RNF213 can be differently altered to predispose distinct populations to dissimilar neurovascular conditions, highlighting the importance of a population's background in genetic studies of heterogeneous disease.

Mutations in CAPN1 Cause Autosomal-Recessive Hereditary Spastic Paraplegia.

Hereditary spastic paraplegia (HSP) is a genetically and clinically heterogeneous disease characterized by spasticity and weakness of the lower limbs with or without additional neurological symptoms. Although more than 70 genes and genetic loci have been implicated in HSP, many families remain genetically undiagnosed, suggesting that other genetic causes of HSP are still to be identified. HSP can be inherited in an autosomal-dominant, autosomal-recessive, or X-linked manner. In the current study, we performed whole-exome sequencing to analyze a total of nine affected individuals in three families with autosomal-recessive HSP. Rare homozygous and compound-heterozygous nonsense, missense, frameshift, and splice-site mutations in CAPN1 were identified in all affected individuals, and sequencing in additional family members confirmed the segregation of these mutations with the disease (spastic paraplegia 76 [SPG76]). CAPN1 encodes calpain 1, a protease that is widely present in the CNS. Calpain 1 is involved in synaptic plasticity, synaptic restructuring, and axon maturation and maintenance. Three models of calpain 1 deficiency were further studied. In Caenorhabditis elegans, loss of calpain 1 function resulted in neuronal and axonal dysfunction and degeneration. Similarly, loss-of-function of the Drosophila melanogaster ortholog calpain B caused locomotor defects and axonal anomalies. Knockdown of calpain 1a, a CAPN1 ortholog in Danio rerio, resulted in abnormal branchiomotor neuron migration and disorganized acetylated-tubulin axonal networks in the brain. The identification of mutations in CAPN1 in HSP expands our understanding of the disease causes and potential mechanisms.

SMPD1 mutations, activity, and α-synuclein accumulation in Parkinson's disease.

BACKGROUND: SMPD1 (acid-sphingomyelinase) variants have been associated with Parkinson's disease in recent studies. The objective of this study was to further investigate the role of SMPD1 mutations in PD. METHODS: SMPD1 was sequenced in 3 cohorts (Israel Ashkenazi Jewish cohort, Montreal/Montpellier, and New York), including 1592 PD patients and 975 controls. Additional data were available for 10,709 Ashkenazi Jewish controls. Acid-sphingomyelinase activity was measured by a mass spectrometry-based assay in the New York cohort. α-Synuclein levels were measured in vitro following CRISPR/Cas9-mediated knockout and siRNA knockdown of SMPD1 in HeLa and BE(2)-M17 cells. Lysosomal localization of acid-sphingomyelinase with different mutations was studied, and in silico analysis of their effect on acid-sphingomyelinase structure was performed. RESULTS: SMPD1 mutations were associated with PD in the Ashkenazi Jewish cohort, as 1.4% of PD patients carried the p.L302P or p.fsP330 mutation, compared with 0.37% in 10,709 Ashkenazi Jewish controls (OR, 3.7; 95%CI, 1.6-8.2; P = 0.0025). In the Montreal/Montpellier cohort, the p.A487V variant was nominally associated with PD (1.5% versus 0.14%; P = 0.0065, not significant after correction for multiple comparisons). Among PD patients, reduced acid-sphingomyelinase activity was associated with a 3.5- to 5.8-year earlier onset of PD in the lowest quartile versus the highest quartile of acid-sphingomyelinase activity (P = 0.01-0.001). We further demonstrated that SMPD1 knockout and knockdown resulted in increased α-synuclein levels in HeLa and BE(2)-M17 dopaminergic cells and that the p.L302P and p.fsP330 mutations impair the traffic of acid-sphingomyelinase to the lysosome. CONCLUSIONS: Our results support an association between SMPD1 variants, acid-sphingomyelinase activity, and PD. Furthermore, they suggest that reduced acid-sphingomyelinase activity may lead to α-synuclein accumulation. © 2019 International Parkinson and Movement Disorder Society.

Cognitive and Psychiatric Evaluation in SYNE1 Ataxia.

SYNE1 gene mutations were identified as a cause of late-onset pure cerebellar syndrome. Non-cerebellar symptoms, including cognitive impairment, were already described in this condition. The aim of this study was to perform a detailed cognitive and psychiatric description of patients with SYNE1 gene mutations. We performed neuropsychological and psychiatric evaluations of six patients with SYNE1 ataxia and compared their performance with 18 normal controls paired for age and education level. SYNE1 ataxia patients present cognitive dysfunction, characterized by impairment in attention and processing speed domains. Otherwise, the psychiatric assessment reported low levels of overall behavioral symptoms with only some minor anxiety-related complaints. Although this is a small sample of patients, these results suggest that SYNE1 ataxia patients may represent a model to investigate effects of cerebellar degeneration in higher hierarchical cognitive functions. For further studies, abstract thinking impairment in schizophrenia may be related to dysfunction in cerebellum pathways.

Exome sequencing of sporadic childhood-onset schizophrenia suggests the contribution of X-linked genes in males.

Childhood-onset schizophrenia (COS) is a rare and severe form of schizophrenia, defined as having an onset before the age of 13. The male COS cases have a slightly younger age of onset than female cases. They also present with a higher rate of comorbid developmental disorders. These sex differences are not explained by the frequency of chromosomal abnormalities, and the contribution of other forms of genetic variations remains unestablished. Using a whole-exome sequencing approach, we examined 12 COS trios where the unaffected parents had an affected male child. The sequencing data enabled us to test if the hemizygous variants, transmitted from the unaffected carrying mother, could mediate the phenotype (X-linked recessive inheritance model). Our results revealed that affected children have a significantly greater number of X-linked rare variants than their unaffected fathers. The variants identified in the male probands were mostly found in genes previously linked to other neuropsychiatric diseases like autism, intellectual disability, and epilepsy, including LUZP4, PCDH19, RPS6KA3, and OPHN1. The level of expression of the genes was assessed at different developmental periods in normal brain using the BrainSpan database. This approach revealed that some of them were expressed earlier in males than in females, consistent with the younger age of onset in male COS. In conclusion, this article suggests that X-linked genes might play a role in the pathophysiology of COS. Candidate genes detailed here could explain the higher level of comorbidities and the earlier age of onset observed in a subset of the male COS cases.

Full sequencing and haplotype analysis of MAPT in Parkinson's disease and rapid eye movement sleep behavior disorder.

BACKGROUND: MAPT haplotypes are associated with PD, but their association with rapid eye movement sleep behavior disorder is unclear. OBJECTIVE: To study the role of MAPT variants in rapid eye movement sleep behavior disorder. METHODS: Two cohorts were included: (A) PD (n = 600), rapid eye movement sleep behavior disorder (n = 613) patients, and controls (n = 981); (B) dementia with Lewy bodies patients with rapid eye movement sleep behavior disorder (n = 271) and controls (n = 950). MAPT-associated variants and the entire coding sequence of MAPT were analyzed. Age-, sex-, and ethnicity-adjusted analyses were performed to examine the association between MAPT, PD, and rapid eye movement sleep behavior disorder. RESULTS: MAPT-H2 variants were associated with PD (odds ratios: 0.62-0.65; P = 0.010-0.019), but not with rapid eye movement sleep behavior disorder. In PD, the H1 haplotype odds ratio was 1.60 (95% confidence interval: 1.12-2.28; P = 0.009), and the H2 odds ratio was 0.68 (95% confidence interval: 0.48-0.96; P = 0.03). The H2/H1 haplotypes were not associated with rapid eye movement sleep behavior disorder. CONCLUSIONS: Our results confirm the protective effect of the MAPT-H2 haplotype in PD, and define its components. Furthermore, our results suggest that MAPT does not play a major role in rapid eye movement sleep behavior disorder, emphasizing different genetic background than in PD in this locus. © 2018 International Parkinson and Movement Disorder Society.

FOXP1-related intellectual disability syndrome: a recognisable entity.

BACKGROUND: Mutations in forkhead box protein P1 (FOXP1) cause intellectual disability (ID) and specific language impairment (SLI), with or without autistic features (MIM: 613670). Despite multiple case reports no specific phenotype emerged so far. METHODS: We correlate clinical and molecular data of 25 novel and 23 previously reported patients with FOXP1 defects. We evaluated FOXP1 activity by an in vitro luciferase model and assessed protein stability in vitro by western blotting. RESULTS: Patients show ID, SLI, neuromotor delay (NMD) and recurrent facial features including a high broad forehead, bent downslanting palpebral fissures, ptosis and/or blepharophimosis and a bulbous nasal tip. Behavioural problems and autistic features are common. Brain, cardiac and urogenital malformations can be associated. More severe ID and NMD, sensorineural hearing loss and feeding difficulties are more common in patients with interstitial 3p deletions (14 patients) versus patients with monogenic FOXP1 defects (34 patients). Mutations result in impaired transcriptional repression and/or reduced protein stability. CONCLUSIONS: FOXP1-related ID syndrome is a recognisable entity with a wide clinical spectrum and frequent systemic involvement. Our data will be helpful to evaluate genotype-phenotype correlations when interpreting next-generation sequencing data obtained in patients with ID and/or SLI and will guide clinical management.