Rapid improvements in sequencing and array-based platforms are resulting in a flood of diverse genome-wide data, including data from exome and whole-genome sequencing, epigenetic surveys, expression profiling of coding and noncoding RNAs, single nucleotide polymorphism (SNP) and copy number profiling, and functional assays. Analysis of these large, diverse data sets holds the promise of a more comprehensive understanding of the genome and its relation to human disease. Experienced and knowledgeable human review is an essential component of this process, complementing computational approaches. This calls for efficient and intuitive visualization tools able to scale to very large data sets and to flexibly integrate multiple data types, including clinical data. However, the sheer volume and scope of data pose a significant challenge to the development of such tools.

Integrative Genomics Viewer

Pierre Szepetowski and colleagues report the identification of mutations in GRIN2A in individuals with acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

GRIN2A mutations in acquired epileptic aphasia and related childhood focal epilepsies and encephalopathies with speech and language dysfunction.

Autism spectrum disorders (ASD) are increasingly common neurodevelopmental disorders defined clinically by a triad of features including impairment in social interaction, impairment in communication in social situations and restricted and repetitive patterns of behavior and interests, with considerable phenotypic heterogeneity among individuals. Although heritability estimates for ASD are high, conventional genetic-based efforts to identify genes involved in ASD have yielded only few reproducible candidate genes that account for only a small proportion of ASDs. There is mounting evidence to suggest environmental and epigenetic factors play a stronger role in the etiology of ASD than previously thought. To begin to understand the contribution of epigenetics to ASD, we have examined DNA methylation (DNAm) in a pilot study of postmortem brain tissue from 19 autism cases and 21 unrelated controls, among three brain regions including dorsolateral prefrontal cortex, temporal cortex and cerebellum. We measured over 485,000 CpG loci across a diverse set of functionally relevant genomic regions using the Infinium HumanMethylation450 BeadChip and identified four genome-wide significant differentially methylated regions (DMRs) using a bump hunting approach and a permutation-based multiple testing correction method. We replicated 3/4 DMRs identified in our genome-wide screen in a different set of samples and across different brain regions. The DMRs identified in this study represent suggestive evidence for commonly altered methylation sites in ASD and provide several promising new candidate genes.

Common DNA methylation alterations in multiple brain regions in autism.

Next-generation sequencing has identified mutations in the PRRT2 (proline-rich transmembrane protein 2) gene as the leading cause for a wide and yet evolving spectrum of paroxysmal diseases. PRRT2 mutations are found in the majority of patients with benign familial infantile epilepsy, infantile convulsions and choreoathetosis and paroxysmal kinesigenic dyskinesia, confirming a common disease spectrum that had previously been suggested based on gene linkage analyses and shared clinical features. Beyond these clinical entities, PRRT2 mutations have been described in other childhood-onset movement disorders, different forms of seizures, headache disorders, and intellectual disability. PRRT2 encodes a protein that is expressed in the central nervous system and is thought to be involved in the modulation of synaptic neurotransmitter release. The vast majority of mutations lead to a truncated protein or no protein at all and thus to a haploinsufficient state. The subsequent reduction of PRRT2 protein may lead to altered synaptic neurotransmitter release and dysregulated neuronal excitability in various regions of the brain, resulting in paroxysmal movement disorders and seizure phenotypes. In this review, we examine the genetics and neurobiology of PRRT2 and summarize the evolving clinical and molecular spectrum of PRRT2-associated diseases. Through a comprehensive review of 1444 published cases, we provide a detailed assessment of the demographics, disease characteristics and genetic findings of patients with PRRT2 mutations. Benign familial infantile epilepsy (41.7%; n = 602), paroxysmal kinesigenic dyskinesia (38.7%; n = 560) and infantile convulsions and choreoathetosis (14.3%; n = 206) constitute the vast majority of PRRT2-associated diseases, leaving 76 patients (5.3%) with a different primary diagnosis. A positive family history is present in 89.1% of patients; and PRRT2 mutations are familial in 87.1% of reported cases. Seventy-three different disease-associated PRRT2 mutations (35 truncating, 22 missense, three extension mutations, six putative splice site changes, and seven changes that lead to a complete PRRT2 deletion) have been described to date, with the c.649dupC frameshift mutation accounting for the majority of cases (78.5%). Expanding the genetic landscape, 15 patients with biallelic PRRT2 mutations and six patients with 16p11.2 microdeletions and a paroxysmal kinesigenic dyskinesia phenotype have been reported. Probing the phenotypic boundaries of PRRT2-associated disorders, several movement, seizure and headache disorders have been linked to PRRT2 mutations in a subset of patients. Of these, hemiplegic migraine emerges as a novel PRRT2-associated phenotype. With this comprehensive review of PRRT2-associated diseases, we hope to provide a scientific resource for informing future research, both in laboratory models and in clinical studies.

/pdf/the-evolving-spectrum-of-prrt2-associated-paroxysmal-1wfjeiovcg.pdf

The evolving spectrum of PRRT2-associated paroxysmal diseases.

Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.

Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.

https://www.cell.com/cell-reports/pdf/S2211-1247(11)00006-4.pdf

Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions

To the Editor: We read with interest the article by Ellis et al1Ellis C.N. Neville S.J. Sayyouh M. et al.Epicardial adipose tissue volume is greater in men with severe psoriasis, implying an increased cardiovascular disease risk: a cross-sectional study.J Am Acad Dermatol. 2022; 86: 535-543Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and believe that a few matters are worthy of discussion. First, models in this study were adjusted by age, sex, body mass index, hypertension, dyslipidemia, elevated fasting blood glucose, high-sensitivity C-reactive protein, current smoker, family history of premature cardiovascular diseases, and epicardial adipose tissue volume (EAT-V). We suggest adding confounders such as gout, body fat, exercise frequency, alcohol consumption, and fatty liver because these are also considered as cardiovascular risk factors and, thus, their inclusion in the study may result in confounding bias. In addition, individuals exhibiting the common comorbidities found in patients with psoriasis, such as inflammatory bowel disease, should be taken into consideration when designing the exclusion criteria of the study.2Loganathan A. Kamalaraj N. El-Haddad C. Pile K. Systematic review and meta-analysis on prevalence of metabolic syndrome in psoriatic arthritis, rheumatoid arthritis and psoriasis.Int J Rheum Dis. 2021; 24: 1112-1120Crossref PubMed Scopus (7) Google Scholar The study by Ellis et al1Ellis C.N. Neville S.J. Sayyouh M. et al.Epicardial adipose tissue volume is greater in men with severe psoriasis, implying an increased cardiovascular disease risk: a cross-sectional study.J Am Acad Dermatol. 2022; 86: 535-543Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar has shown a statistically insignificant relationship between psoriasis and changes in EAT-V levels in women. However, postmenopausal women have been shown to have an elevated risk of psoriasis3Ceovic R. Mance M. Bukvic Mokos Z. Svetec M. Kostovic K. Stulhofer Buzina D. Psoriasis: female skin changes in various hormonal stages throughout life–puberty, pregnancy, and menopause.BioMed Res Int. 2013; 2013571912Crossref PubMed Scopus (32) Google Scholar and higher levels of EAT-V4El Khoudary S.R. Shields K.J. Janssen I. et al.Cardiovascular fat, menopause, and sex hormones in women: the SWAN cardiovascular fat ancillary study.J Clin Endocrinol Metab. 2015; 100: 3304-3312Crossref PubMed Scopus (52) Google Scholar than those in premenopausal women because of hormonal changes in the body. Therefore, we are concerned because menopause may have affected the accuracy of the data collected as a confounding factor. That being said, because coronary artery disease is a leading cause of death in women and because psoriasis is highly associated with cardiovascular disease,5Chen Z. Xu Y. Chen M. et al.Gout augments the risk of cardiovascular disease in patients with psoriasis: a population-based cohort study.Front Immunol. 2021; 12703119Google Scholar we believe that research on the relationship between psoriasis and EAT-V levels in women is needed. Therefore, we suggest future similar studies to be focused on the relationship between psoriasis and EAT-V levels in postmenopausal women so as to assist in controlling the risk factors of coronary artery disease in women. None disclosed. 

Correspondence to Charles N. Ellis et al Epicardial adipose tissue volume is greater in men with severe psoriasis, implying an increased cardiovascular disease risk: A cross-sectional study.

Wei Ling Lee

Papers

Mutations in the Gene PRRT2 Cause Paroxysmal Kinesigenic Dyskinesia with Infantile Convulsions

Correspondence to Charles N. Ellis et al Epicardial adipose tissue volume is greater in men with severe psoriasis, implying an increased cardiovascular disease risk: A cross-sectional study.