American Journal of Medical Genetics Part B: Neuropsychiatric Genetics最新文献

{"title":"The role of the gut microbiota in patients with Kleefstra syndrome","authors":"Mirjam Bloemendaal,&nbsp;Priscilla Vlaming,&nbsp;Anneke de Boer,&nbsp;Karlijn Vermeulen-Kalk,&nbsp;Arianne Bouman,&nbsp;Tjitske Kleefstra,&nbsp;Alejandro Arias Vasquez","doi":"10.1002/ajmg.b.32926","DOIUrl":"10.1002/ajmg.b.32926","url":null,"abstract":"<p>Kleefstra Syndrome (KS) is a rare monogenetic syndrome, caused by haploinsufficiency of the euchromatic histone methyl transferase 1 (EHMT1) gene, an important regulator of neurodevelopment. The clinical features of KS include intellectual disability, autistic behavior and gastrointestinal problems. The gut microbiota, an important modifier of the gut-brain-axis, may constitute an unexplored mechanism underlying clinical KS variation. We investigated the gut microbiota composition of 23 individuals with KS (patients) and 40 of their family members, to test whether (1) variation in the gut microbiota associates with KS diagnosis and (2) variation within the gut microbiota relates with KS syndrome symptoms. Both alpha and beta diversity of patients were different from their family members. Genus <i>Coprococcus</i> 3 was lower in abundance in patients compared to family members. Moreover, abundance of genus <i>Merdibacter</i> was lower in patients versus family members, but only in participants reporting intestinal complaints. Within the patient group, behavioral problems explained 7% of beta diversity variance. Also, within this group, we detected higher levels of <i>Atopobiaceae – uncultured</i> and <i>Ruminococcaceae</i> Subdoligranulum associated with higher symptom severity. These significant signatures in the gut microbiota composition in patients with KS suggest that microbiota differences are part of the KS phenotype.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"192 7-8","pages":"124-138"},"PeriodicalIF":2.8,"publicationDate":"2023-01-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32926","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10549381","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Karl Grassmann's 1896 paper “critical overview of contemporary theories of the heredity of the psychoses”","authors":"Kenneth S. Kendler,&nbsp;Astrid Klee","doi":"10.1002/ajmg.b.32925","DOIUrl":"10.1002/ajmg.b.32925","url":null,"abstract":"<p>Four years before the rediscovery of Mendel's work in 1900, Karl Grassmann published a detailed, scholarly review of the heredity of psychosis which we here review. A full translation is in the appendix. We emphasize seven major conclusions from this review. First, while recognizing the key importance of heredity in the etiology of psychosis. Grassmann was critical of many of the highly speculative extant theories. Second, he reviewed most of the major methodologic concerns in the literature from what kinds of heredity to investigate to the problems with the global use of insanity as a diagnostic category. Third, he discussed in detail genetic theories associated with Degeneration theory, maintaining considerable skepticism. Fourth, he recognized nongenetic contribution to familial transmission. Fifth, he reviewed evidence for both homogeneous and heterogeneous transmission of forms of mental illness in families, suggesting that both were important. Sixth, while he noted that mania, melancholia, and cyclothymia commonly replaced each other in families, Verrücktheit (delusional psychoses) rarely co-segregated in families with these mood disorders. Seventh, Grassmann, like other 19th century writers, saw relatives to be of value only in assessing the level of hereditary predisposition in patients and had limited appreciation of the need for controlled studies.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"192 3-4","pages":"41-52"},"PeriodicalIF":2.8,"publicationDate":"2022-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32925","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9334835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Polygenic and environmental determinants of tics in the Avon Longitudinal Study of Parents and Children","authors":"Mohamed Abdulkadir,&nbsp;Jay A. Tischfield,&nbsp;Gary A. Heiman,&nbsp;Pieter J. Hoekstra,&nbsp;Andrea Dietrich","doi":"10.1002/ajmg.b.32924","DOIUrl":"10.1002/ajmg.b.32924","url":null,"abstract":"<p>Tourette syndrome (TS) is caused by multiple genetic and environmental factors. Yet, little is known about the interplay of these factors in the occurrence of tics. We investigated whether polygenic risk score (PRS) of TS and pregnancy-related factors together enhance the explained variance of tic occurrence in the Avon Longitudinal Study of Parents and Children (<i>N</i>_cases = 612; <i>N</i>_controls = 4,201; 50% male; mean age 13.8 years). We included a cumulative adverse pregnancy risk score, maternal anxiety and depression, and maternal smoking and alcohol use during pregnancy. We investigated possible joint effects of genetic and pregnancy-related risk factors using a multivariable approach, and explored mediation effects between the pregnancy-related risk factors in explaining tic presence. The PRS and the cumulative adverse pregnancy risk score, maternal anxiety, or maternal depression explained significantly more variance of tic presence compared to models including only the PRS. Furthermore, we found that the cumulative adverse pregnancy risk score mediated the association between several pregnancy-related factors (maternal anxiety, depression, and smoking) and tics. The combination of a PRS and pregnancy-related risk factors explained more variance of tics in a general population cohort compared to studying these factors in isolation.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"192 5-6","pages":"73-84"},"PeriodicalIF":2.8,"publicationDate":"2022-12-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10247895/pdf/nihms-1885094.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9912519","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multivariate analyses of molecular genetic associations between childhood psychopathology and adult mood disorders and related traits","authors":"Wonuola A. Akingbuwa,&nbsp;Anke R. Hammerschlag,&nbsp;Andrea G. Allegrini,&nbsp;Hannah Sallis,&nbsp;Ralf Kuja-Halkola,&nbsp;Kaili Rimfeld,&nbsp;Paul Lichtenstein,&nbsp;Sebastian Lundstrom,&nbsp;Marcus R. Munafò,&nbsp;Robert Plomin,&nbsp;Michel G. Nivard,&nbsp;Meike Bartels,&nbsp;Christel M. Middeldorp","doi":"10.1002/ajmg.b.32922","DOIUrl":"10.1002/ajmg.b.32922","url":null,"abstract":"<p>Ubiquitous associations have been detected between different types of childhood psychopathology and polygenic risk scores based on adult psychiatric disorders and related adult outcomes, indicating that genetic factors partly explain the association between childhood psychopathology and adult outcomes. However, these analyses in general do not take into account the correlations between the adult trait and disorder polygenic risk scores. This study aimed to further clarify the influence of genetic factors on associations between childhood psychopathology and adult outcomes by accounting for these correlations. Using a multivariate multivariable regression, we analyzed associations of childhood attention-deficit/hyperactivity disorder (ADHD), internalizing, and social problems, with polygenic scores (PGS) of adult disorders and traits including major depression, bipolar disorder, subjective well-being, neuroticism, insomnia, educational attainment, and body mass index (BMI), derived for 20,539 children aged 8.5–10.5 years. After correcting for correlations between the adult phenotypes, major depression PGS were associated with all three childhood traits, that is, ADHD, internalizing, and social problems. In addition, BMI PGS were associated with ADHD symptoms and social problems, while neuroticism PGS were only associated with internalizing problems and educational attainment PGS were only associated with ADHD symptoms. PGS of bipolar disorder, subjective well-being, and insomnia were not associated with any childhood traits. Our findings suggest that associations between childhood psychopathology and adult traits like insomnia and subjective well-being may be primarily driven by genetic factors that influence adult major depression. Additionally, specific childhood phenotypes are genetically associated with educational attainment, BMI and neuroticism.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"192 1-2","pages":"3-12"},"PeriodicalIF":2.8,"publicationDate":"2022-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32922","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10141965","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Influence of antidepressant treatment on SLC6A4 methylation in Korean patients with major depression","authors":"Young Kyung Moon,&nbsp;Hyeseung Kim,&nbsp;Seonwoo Kim,&nbsp;Shinn-Won Lim,&nbsp;Doh Kwan Kim","doi":"10.1002/ajmg.b.32921","DOIUrl":"10.1002/ajmg.b.32921","url":null,"abstract":"<p>Genetic variation of the serotonin transporter gene (<i>SLC6A4</i>) has been suggested as potential mediator for antidepressant response in patients with depression. This study aimed to determine whether DNA methylation in <i>SLC6A4</i> changes after antidepressant treatment and whether it affects treatment response in patients with depression. Overall, 221 Korean patients with depression completed 6 weeks of selective serotonin reuptake inhibitor (SSRI) monotherapy. DNA was extracted from venous blood pre- and post-treatment, and DNA methylation was analyzed using polymerase chain reaction. We used Wilcoxon's signed-rank test to verify the difference in methylation after treatment. Treatment response was assessed using the 17-item Hamilton Depression Rating Scale, and mRNA levels were quantified.</p><p>After adjusting for relevant covariates, DNA methylation was significantly altered in specific CpG sites in <i>SLC6A4</i> (<i>p</i> &lt; .001 in CpG3, CpG4, and CpG5) following 6 weeks of treatment. Methylation change's magnitude (ΔDNA methylation) after drug treatment was not associated with treatment response or mRNA level change. SSRI antidepressants can influence <i>SLC6A4</i> methylation in patients with depression. However, ΔDNA methylation at CpG3, CpG4, and CpG5 in <i>SLC6A4</i> was not associated with treatment response. Future studies should investigate the integrative effect of other genetic variants and CpG methylation on gene transcription and antidepressant treatment response.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"192 1-2","pages":"28-37"},"PeriodicalIF":2.8,"publicationDate":"2022-09-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10377273","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Within subject cross-tissue analyzes of epigenetic clocks in substance use disorder postmortem brain and blood","authors":"Brenda Cabrera-Mendoza,&nbsp;Laura Stertz,&nbsp;Katherine Najera,&nbsp;Sudhakar Selvaraj,&nbsp;Antonio L. Teixeira,&nbsp;Thomas D. Meyer,&nbsp;Gabriel R. Fries,&nbsp;Consuelo Walss-Bass","doi":"10.1002/ajmg.b.32920","DOIUrl":"10.1002/ajmg.b.32920","url":null,"abstract":"<p>There is a possible accelerated biological aging in patients with substance use disorders (SUD). The evaluation of epigenetic clocks, which are accurate estimators of biological aging based on DNA methylation changes, has been limited to blood tissue in patients with SUD. Consequently, the impact of biological aging in the brain of individuals with SUD remains unknown. In this study, we evaluated multiple epigenetic clocks (DNAmAge, DNAmAgeHannum, DNAmAgeSkinBlood, DNAmPhenoAge, DNAmGrimAge, and DNAmTL) in individuals with SUD (<i>n</i> = 42), including alcohol (<i>n</i> = 10), opioid (<i>n</i> = 19), and stimulant use disorder (<i>n</i> = 13), and controls (<i>n</i> = 10) in postmortem brain (prefrontal cortex) and blood tissue obtained from the same individuals. We found a higher DNAmPhenoAge (<i>β</i> = 0.191, <i>p</i>-value = 0.0104) and a nominally lower DNAmTL (<i>β</i> = −0.149, <i>p</i>-value = 0.0603) in blood from individuals with SUD compared to controls. SUD subgroup analysis showed a nominally lower brain DNAmTL in subjects with alcohol use disorder, compared to stimulant use disorder and controls (<i>β</i> = 0.0150, <i>p</i>-value = 0.087). Cross-tissue analyzes indicated a lower blood DNAmTL and a higher blood DNAmAge compared to their respective brain values in the SUD group. This study highlights the relevance of tissue specificity in biological aging studies and suggests that peripheral measures of epigenetic clocks in SUD may depend on the specific type of drug used.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"192 1-2","pages":"13-27"},"PeriodicalIF":2.8,"publicationDate":"2022-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32920","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10353501","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetics and epigenetics of self-injurious thoughts and behaviors: Systematic review of the suicide literature and methodological considerations","authors":"Salahudeen Mirza,&nbsp;Anna R. Docherty,&nbsp;Amanda Bakian,&nbsp;Hilary Coon,&nbsp;Jair C. Soares,&nbsp;Consuelo Walss-Bass,&nbsp;Gabriel R. Fries","doi":"10.1002/ajmg.b.32917","DOIUrl":"10.1002/ajmg.b.32917","url":null,"abstract":"<p>Suicide is a multifaceted and poorly understood clinical outcome, and there is an urgent need to advance research on its phenomenology and etiology. Epidemiological studies have demonstrated that suicidal behavior is heritable, suggesting that genetic and epigenetic information may serve as biomarkers for suicide risk. Here we systematically review the literature on genetic and epigenetic alterations observed in phenotypes across the full range of self-injurious thoughts and behaviors (SITB). We included 577 studies focused on genome-wide and epigenome-wide associations, candidate genes (SNP and methylation), noncoding RNAs, and histones. Convergence of specific genes is limited across units of analysis, although pathway-based analyses do indicate nervous system development and function and immunity/inflammation as potential underlying mechanisms of SITB. We provide suggestions for future work on the genetic and epigenetic correlates of SITB with a specific focus on measurement issues.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 7-8","pages":"221-246"},"PeriodicalIF":2.8,"publicationDate":"2022-08-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10656998","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ADHD-associated PARK2 copy number variants: A pilot study on gene expression and effects of supplementary deprivation in patient-derived cell lines","authors":"Franziska Radtke,&nbsp;Viola Stella Palladino,&nbsp;Rhiannon V. McNeill,&nbsp;Andreas G. Chiocchetti,&nbsp;Denise Haslinger,&nbsp;Matthias Leyh,&nbsp;Danijel Gersic,&nbsp;Markus Frank,&nbsp;Lena Grünewald,&nbsp;Stephan Klebe,&nbsp;Oliver Brüstle,&nbsp;Katharina Günther,&nbsp;Frank Edenhofer,&nbsp;Thorsten M. Kranz,&nbsp;Andreas Reif,&nbsp;Sarah Kittel-Schneider","doi":"10.1002/ajmg.b.32918","DOIUrl":"10.1002/ajmg.b.32918","url":null,"abstract":"<p>Recent studies show an association of Parkin RBR E3 ubiquitin protein ligase (<i>PARK2</i>) copy number variations (CNVs) with attention deficit hyperactivity disorder (ADHD). The aim of our pilot study to investigate gene expression associated with <i>PARK2</i> CNVs in human-derived cellular models. We investigated gene expression in fibroblasts, hiPSC and dopaminergic neurons (DNs) of ADHD <i>PARK2</i> deletion and duplication carriers by qRT PCR compared with healthy and ADHD cell lines without <i>PARK2</i> CNVs. The selected 10 genes of interest were associated with oxidative stress response (<i>TP53, NQO1,</i> and <i>NFE2L2</i>), ubiquitin pathway (<i>UBE3A, UBB, UBC,</i> and <i>ATXN3</i>) and with a function in mitochondrial quality control (<i>PINK1, MFN2,</i> and <i>ATG5</i>). Additionally, an exploratory RNA bulk sequencing analysis in DNs was conducted. Nutrient deprivation as a supplementary deprivation stress paradigm was used to enhance potential genotype effects. At baseline, in fibroblasts, hiPSC, and DNs, there was no significant difference in gene expression after correction for multiple testing. After nutrient deprivation in fibroblasts NAD(P)H-quinone-dehydrogenase 1 (<i>NQO1</i>) expression was significantly increased in <i>PARK2</i> CNV carriers. In a multivariate analysis, ubiquitin C (<i>UBC</i>) was significantly upregulated in fibroblasts of <i>PARK2</i> CNV carriers. RNA sequencing analysis of DNs showed the strongest significant differential regulation in Neurontin (<i>NNAT</i>) at baseline and after nutrient deprivation. Our preliminary results suggest differential gene expression in pathways associated with oxidative stress, ubiquitine-proteasome, immunity, inflammation, cell growth, and differentiation, excitation/inhibition modulation, and energy metabolism in <i>PARK2</i> CNV carriers compared to wildtype healthy controls and ADHD patients.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 7-8","pages":"257-270"},"PeriodicalIF":2.8,"publicationDate":"2022-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32918","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9189804","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cross-sectional and longitudinal associations between gut microbiota composition and cognition in the second year of life: Findings from the Child Health and Resident Microbes study","authors":"Misa Matsuyama,&nbsp;Nida Murtaza,&nbsp;Mark Morrison,&nbsp;Peter S.W. Davies,&nbsp;Rebecca J. Hill,&nbsp;Amy Loughman","doi":"10.1002/ajmg.b.32915","DOIUrl":"10.1002/ajmg.b.32915","url":null,"abstract":"<p>The relationship between the gut microbiota and brain function are receiving increasing research attention. Studies investigating gut microbiota and early childhood neurocognition are limited, particularly in longitudinal measurements. We examined cross-sectional relationships between gut microbiota of a cohort of otherwise healthy children using 16S rRNA sequencing and their cognitive development measured with Bayley's Scales of Infant Development III at 24 months of age (<i>n</i> = 43), and longitudinal relationships between gut microbiota composition at 12 months (<i>n</i> = 41) of age and neurodevelopment at 24 months of age. Associations between gut microbiota characteristics and cognitive development were observed both cross-sectionally and longitudinally, notably with butyrate producing bacteria among some children. Bacterial diversity varied between cross-sectional and longitudinal observations, where the gut microbiota community of children with lower cognitive scores had a trend toward higher alpha diversity, whereas, in the longitudinal observation, a trend toward reduced alpha diversity was observed. This study is limited by a small sample size and its exploratory nature. Yet, the study contributes to knowledge in the gut microbiota characteristics and early life neurodevelopment, a field of study which is underexplored, presenting opportunities for future larger specific studies.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 7-8","pages":"285-292"},"PeriodicalIF":2.8,"publicationDate":"2022-08-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/ajmg.b.32915","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"88393747","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CELSR1 variants are associated with partial epilepsy of childhood","authors":"Zheng Chen,&nbsp;Sheng Luo,&nbsp;Zhi-Gang Liu,&nbsp;Yan-Chun Deng,&nbsp;Su-Li He,&nbsp;Xiao-Rong Liu,&nbsp;Yong-Hong Yi,&nbsp;Jie Wang,&nbsp;Liang-Di Gao,&nbsp;Bing-Mei Li,&nbsp;Zhi-Jun Wu,&nbsp;Zi-Long Ye,&nbsp;De-Hai Liang,&nbsp;Wen-Jun Bian,&nbsp;Wei-Ping Liao,&nbsp;For the China Epilepsy Gene 1.0 Project","doi":"10.1002/ajmg.b.32916","DOIUrl":"10.1002/ajmg.b.32916","url":null,"abstract":"<p><i>CELSR1</i> gene, encoding cadherin EGF LAG seven-pass G-type receptor 1, is mainly expressed in neural stem cells during the embryonic period. It plays an important role in neurodevelopment. However, the relationship between <i>CELSR1</i> and disease of the central nervous system has not been defined. In this study, we performed trios-based whole-exome sequencing in a cohort of 356 unrelated cases with partial epilepsy without acquired causes and identified <i>CELSR1</i> variants in six unrelated cases. The variants included one de novo heterozygous nonsense variant, one de novo heterozygous missense variant, and four compound heterozygous missense variants that had one variant was located in the extracellular region and the other in the cytoplasm. The patients with biallelic variants presented severe epileptic phenotypes, whereas those with heterozygous variants were associated with a mild epileptic phenotype of benign epilepsy with centrotemporal spikes (BECTS). These variants had no or low allele frequency in the gnomAD database. The frequencies of the <i>CELSR1</i> variants in this cohort were significantly higher than those in the control populations. The evidence from ClinGen Clinical-Validity Framework suggested a strong association between <i>CELSR1</i> variants and epilepsy. These findings provide evidence that <i>CELSR1</i> is potentially a candidate pathogenic gene of partial epilepsy of childhood.</p>","PeriodicalId":7673,"journal":{"name":"American Journal of Medical Genetics Part B: Neuropsychiatric Genetics","volume":"189 7-8","pages":"247-256"},"PeriodicalIF":2.8,"publicationDate":"2022-08-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10638384","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}