Intronic FGF14 GAA repeat expansions impact progression and survival in multiple system atrophy.

Partial phenotypic overlap has been suggested between multiple system atrophy and spinocerebellar ataxia 27B, the autosomal dominant ataxia caused by an intronic GAA•TTC repeat expansion in FGF14. In this study, we investigated the frequency of FGF14 GAA•TTC repeat expansion in clinically diagnosed and pathologically confirmed multiple system atrophy cases. We screened 657 multiple system atrophy cases (193 clinically diagnosed and 464 pathologically confirmed) and 1003 controls.

Expanded methylome and quantitative trait loci detection by long-read profiling of personal DNA.

Structural variants (SVs) are omnipresent in human DNA, yet their genotype and methylation statuses are rarely characterized due to previous limitations in genome assembly and detection of modified nucleotides. Also, the extent to which SVs act as methylation quantitative trait loci (SV-mQTLs) is largely unknown. Here, we generated a pangenome graph summarizing SVs in 782 de novo assemblies obtained from Genomic Answers for Kids, capturing 14.

Total plasma cfDNA methylation in pediatric kidney transplant recipients provides insight into acute allograft rejection pathophysiology.

Cell-free DNA (cfDNA) is a marker of organ injury and immune response. DNA methylation is an epigenetic regulator of gene expression. Here, we elucidate total plasma cfDNA methylation from kidney transplant recipients in presence versus absence of rejection.

Complex trait associations in rare diseases and impacts on Mendelian variant interpretation.

Emerging evidence implicates common genetic variation - aggregated into polygenic scores (PGS) - in the onset and phenotypic presentation of rare diseases. Here, we comprehensively map individual polygenic liability for 1102 open-source PGS in a cohort of 3059 probands enrolled in the Genomic Answers for Kids (GA4K) rare disease study, revealing widespread associations between rare disease phenotypes and PGSs for common complex diseases and traits, blood protein levels, and brain and other organ morphological measurements. Using this resource, we demonstrate increased polygenic liability in probands with an inherited candidate disease variant (VUS) compared to unaffected carrier parents.

Pangenome graphs improve the analysis of structural variants in rare genetic diseases.

Rare DNA alterations that cause heritable diseases are only partially resolvable by clinical next-generation sequencing due to the difficulty of detecting structural variation (SV) in all genomic contexts. Long-read, high fidelity genome sequencing (HiFi-GS) detects SVs with increased sensitivity and enables assembling personal and graph genomes. We leverage standard reference genomes, public assemblies (n = 94) and a large collection of HiFi-GS data from a rare disease program (Genomic Answers for Kids, GA4K, n = 574 assemblies) to build a graph genome representing a unified SV callset in GA4K, identify common variation and prioritize SVs that are more likely to cause genetic disease (MAF < 0.

Extravillous trophoblast cell lineage development is associated with active remodeling of the chromatin landscape.

The extravillous trophoblast cell lineage is a key feature of placentation and successful pregnancy. Knowledge of transcriptional regulation driving extravillous trophoblast cell development is limited. Here, we map the transcriptome and epigenome landscape as well as chromatin interactions of human trophoblast stem cells and their transition into extravillous trophoblast cells.

Adverse Maternal Environments Perturb Hepatic DNA Methylome and Transcriptome Prior to the Adult-Onset Non-Alcoholic Fatty Liver Disease in Mouse Offspring.

Exposure to adverse early-life environments (AME) increases the incidence of developing adult-onset non-alcoholic fatty liver disease (NAFLD). DNA methylation has been postulated to link AME and late-onset diseases. This study aimed to investigate whether and to what extent the hepatic DNA methylome was perturbed prior to the development of NAFLD in offspring exposed to AME in mice.

Direct haplotype-resolved 5-base HiFi sequencing for genome-wide profiling of hypermethylation outliers in a rare disease cohort.

Long-read HiFi genome sequencing allows for accurate detection and direct phasing of single nucleotide variants, indels, and structural variants. Recent algorithmic development enables simultaneous detection of CpG methylation for analysis of regulatory element activity directly in HiFi reads. We present a comprehensive haplotype resolved 5-base HiFi genome sequencing dataset from a rare disease cohort of 276 samples in 152 families to identify rare (~0.

Insurance denials and diagnostic rates in a pediatric genomic research cohort.

Purpose: This study aimed to assess the amount and types of clinical genetic testing denied by insurance and the rate of diagnostic and candidate genetic findings identified through research in patients who faced insurance denials.

Methods: Analysis consisted of review of insurance denials in 801 patients enrolled in a pediatric genomic research repository with either no previous genetic testing or previous negative genetic testing result identified through cross-referencing with insurance prior-authorizations in patient medical records. Patients and denials were also categorized by type of insurance coverage.

Immune cell residency in the nasal mucosa may partially explain respiratory disease severity across the age range.

Previous studies focusing on the age disparity in COVID-19 severity have suggested that younger individuals mount a more robust innate immune response in the nasal mucosa after infection with SARS-CoV-2. However, it is unclear if this reflects increased immune activation or increased immune residence in the nasal mucosa. We hypothesized that immune residency in the nasal mucosa of healthy individuals may differ across the age range.

Single-cell analysis of human adipose tissue identifies depot and disease specific cell types.

The complex relationship between metabolic disease risk and body fat distribution in humans involves cellular characteristics which are specific to body fat compartments. Here we show depot-specific differences in the stromal vascual fraction of visceral and subcutaneous adipose tissue by performing single-cell RNA sequencing of tissue specimen from obese individuals. We characterize multiple immune cells, endothelial cells, fibroblasts, adipose and hematopoietic stem cell progenitors.

Correction to: Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome.

Following publication of the original article [1], the authors reported an error in Additional file 1.

H3K27M induces defective chromatin spread of PRC2-mediated repressive H3K27me2/me3 and is essential for glioma tumorigenesis.

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.

Dissecting features of epigenetic variants underlying cardiometabolic risk using full-resolution epigenome profiling in regulatory elements.

Sparse profiling of CpG methylation in blood by microarrays has identified epigenetic links to common diseases. Here we apply methylC-capture sequencing (MCC-Seq) in a clinical population of ~200 adipose tissue and matched blood samples (N~400), providing high-resolution methylation profiling (>1.3 M CpGs) at regulatory elements.

Epigenome data release: a participant-centered approach to privacy protection.

Large-scale epigenome mapping by the NIH Roadmap Epigenomics Project, the ENCODE Consortium and the International Human Epigenome Consortium (IHEC) produces genome-wide DNA methylation data at one base-pair resolution. We examine how such data can be made open-access while balancing appropriate interpretation and genomic privacy. We propose guidelines for data release that both reduce ambiguity in the interpretation of open-access data and limit immediate access to genetic variation data that are made available through controlled access.

Risk of re-identification of epigenetic methylation data: a more nuanced response is needed.

In this letter to the editor, we respond to the recent publication by Philibert et al. Methylation array data can simultaneously identify individuals and convey protected health information: an unrecognized ethical concern (Clinical Epigenetics 2014, 6:28). Further discussion of the issues raised by the risk of re-identification of epigenetic methylation data is needed, and a more nuanced approach should be taken with respect to its implications for data sharing policy than the one provided.

Compensating for literature annotation bias when predicting novel drug-disease relationships through Medical Subject Heading Over-representation Profile (MeSHOP) similarity.

Background: Using annotations to the articles in MEDLINE®/PubMed®, over six thousand chemical compounds with pharmacological actions have been tracked since 1996. Medical Subject Heading Over-representation Profiles (MeSHOPs) quantitatively leverage the literature associated with biological entities such as diseases or drugs, providing the opportunity to reposition known compounds towards novel disease applications.

Methods: A MeSHOP is constructed by counting the number of times each medical subject term is assigned to an entity-related research publication in the MEDLINE database and calculating the significance of the count by comparing against the count of the term in a background set of publications.