'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Fri, 18 Jun 2021 04:37:17 EDT Fri, 18 Jun 2021 04:37:17 EDT jirtle@radonc.duke.edu james001@jirtle.com Postzygotic reproductive isolation established in the endosperm: mechanisms, drivers and relevance. Köhler C, Dziasek K, Del Toro-De León G
Philos Trans R Soc Lond B Biol Sci (Jun 2021)

The endosperm is a developmental innovation of angiosperms that supports embryo growth and germination. Aside from this essential reproductive function, the endosperm fuels angiosperm evolution by rapidly establishing reproductive barriers between incipient species. Specifically, the endosperm prevents hybridization of newly formed polyploids with their non-polyploid progenitors, a phenomenon termed the triploid block. Furthermore, recently diverged diploid species are frequently reproductively isolated by endosperm-based hybridization barriers. Current genetic approaches have revealed a prominent role for epigenetic processes establishing these barriers. In particular, imprinted genes, which are expressed in a parent-of-origin-specific manner, underpin the interploidy barrier in the model species . We will discuss the mechanisms establishing hybridization barriers in the endosperm, the driving forces for these barriers and their impact for angiosperm evolution. This article is part of the theme issue 'How does epigenetics influence the course of evolution?']]> Wed, 31 Dec 1969 19:00:00 EST The role of CTCF in the organization of the centromeric 11p15 imprinted domain interactome. Naveh NSS, Deegan DF, Huhn J, Traxler E, Lan Y, Weksberg R, Ganguly A, Engel N, Kalish JM
Nucleic Acids Res (Jun 2021)

DNA methylation, chromatin-binding proteins, and DNA looping are common components regulating genomic imprinting which leads to parent-specific monoallelic gene expression. Loss of methylation (LOM) at the human imprinting center 2 (IC2) on chromosome 11p15 is the most common cause of the imprinting overgrowth disorder Beckwith-Wiedemann Syndrome (BWS). Here, we report a familial transmission of a 7.6 kB deletion that ablates the core promoter of KCNQ1. This structural alteration leads to IC2 LOM and causes recurrent BWS. We find that occupancy of the chromatin organizer CTCF is disrupted proximal to the deletion, which causes chromatin architecture changes both in cis and in trans. We also profile the chromatin architecture of IC2 in patients with sporadic BWS caused by isolated LOM to identify conserved features of IC2 regulatory disruption. A strong interaction between CTCF sites around KCNQ1 and CDKN1C likely drive their expression on the maternal allele, while a weaker interaction involving the imprinting control region element may impede this connection and mediate gene silencing on the paternal allele. We present an imprinting model in which KCNQ1 transcription is necessary for appropriate CTCF binding and a novel chromatin conformation to drive allele-specific gene expression.]]> Wed, 31 Dec 1969 19:00:00 EST The insecticide permethrin induces transgenerational behavioral changes linked to transcriptomic and epigenetic alterations in zebrafish (Danio rerio). Blanc M, Antczak P, Cousin X, Grunau C, Scherbak N, Rüegg J, Keiter SH
Sci Total Environ (Jul 2021)

The pyrethroid insecticide permethrin is widely used for agricultural and domestic purposes. Previous data indicated that it acts as a developmental neurotoxicant and can induce transgenerational effects in non-target organisms. However, associated underlying mechanisms remain unclear. The aim of this study was to investigate permethrin-related transgenerational effects in the zebrafish model, and to identify possible molecular mechanisms underlying inheritance. Zebrafish (F0) were exposed to permethrin during early-life (2 h post-fertilization up to 28 days). The F1 and F2 offspring generations were obtained by pairing exposed F0 males and females, and were bred unexposed. Locomotor and anxiety behavior were investigated, together with transcriptomic and epigenomic (DNA methylation) changes in brains. Permethrin exposed F0 fish were hypoactive at adulthood, while males from the F1 and F2 generations showed a specific decrease in anxiety-like behavior. In F0, transcriptomic data showed enrichment in pathways related to glutamatergic synapse activity, which may partly underlie the behavioral effects. In F1 and F2 males, dysregulation of similar pathways was observed, including a subset of differentially methylated regions that were inherited from the F0 to the F2 generation and indicated stable dysregulation of glutamatergic signaling. Altogether, the present results provide novel evidence on the transgenerational neurotoxic effects of permethrin, as well as mechanistic insight: a transient exposure induces persistent transcriptional and DNA methylation changes that may translate into transgenerational alteration of glutamatergic signaling and, thus, into behavioral alterations.]]> Wed, 31 Dec 1969 19:00:00 EST Multiplex indexing approach for the detection of DNase I hypersensitive sites in single cells. Gao W, Ku WL, Pan L, Perrie J, Zhao T, Hu G, Wu Y, Zhu J, Ni B, Zhao K
Nucleic Acids Res (06 2021)

Single cell chromatin accessibility assays reveal epigenomic variability at cis-regulatory elements among individual cells. We previously developed a single-cell DNase-seq assay (scDNase-seq) to profile accessible chromatin in a limited number of single cells. Here, we report a novel indexing strategy to resolve single-cell DNase hypersensitivity profiles based on bulk cell analysis. This new technique, termed indexing single-cell DNase sequencing (iscDNase-seq), employs the activities of terminal DNA transferase (TdT) and T4 DNA ligase to add unique cell barcodes to DNase-digested chromatin ends. By a three-layer indexing strategy, it allows profiling genome-wide DHSs for >15 000 single-cells in a single experiment. Application of iscDNase-seq to human white blood cells accurately revealed specific cell types and inferred regulatory transcription factors (TF) specific to each cell type. We found that iscDNase-seq detected DHSs with specific properties related to gene expression and conservation missed by scATAC-seq for the same cell type. Also, we found that the cell-to-cell variation in accessibility computed using iscDNase-seq data is significantly correlated with the cell-to-cell variation in gene expression. Importantly, this correlation is significantly higher than that between scATAC-seq and scRNA-seq, suggesting that iscDNase-seq data can better predict the cellular heterogeneity in gene expression compared to scATAC-seq. Thus, iscDNase-seq is an attractive alternative method for single-cell epigenomics studies.]]> Wed, 31 Dec 1969 19:00:00 EST Accelerated Epigenetic Age in Normal Cognitive Aging of Korean Community-Dwelling Older Adults. Park J, Won CW, Saligan LN, Kim YJ, Kim Y, Lukkahatai N
Biol Res Nurs (Jul 2021)

Epigenetic age acceleration has been studied as a promising biomarker of age-related conditions, including cognitive aging. This pilot study aims to explore potential cognitive aging-related biomarkers by investigating the relationship of epigenetic age acceleration and cognitive function and by examining the epigenetic age acceleration differences between successful cognitive aging (SCA) and normal cognitive aging (NCA) among Korean community-dwelling older adults (CDOAs).]]> Wed, 31 Dec 1969 19:00:00 EST The Acid/Base Characterization of Molecules with Epigenetic Activity. Santibáñez-Morán MG, Medina-Franco JL
ChemMedChem (Jun 2021)

The acidic and basic functional groups in a molecule strongly influence its physicochemical properties, affinity for a macromolecule, pharmacokinetics, and toxicity. For instance, basicity has been correlated with molecular promiscuity, hERG blockade, and phospholipidosis. Nonetheless, no systematic characterization of the acid/base profile of epigenomic databases has been reported. This study describes an analysis of the acidic ionization constant distribution of a library of 7820 compounds with reported activity against epigenetic targets. Furthermore, the epigenomics database's acid/base profile was compared to the reference libraries of food chemicals, natural products, and approved drugs. It was found that the acid/base profile of histone lysine demethylase ligands is more similar to previously approved drugs, and histone acetyltransferase ligands have acidic and basic functional groups largely found in food chemicals and natural products; this support the potential of these libraries for finding new epigenetic inhibitors.]]> Wed, 31 Dec 1969 19:00:00 EST Reproductive Outcomes from Maternal Loss of Nlrp2 Are Not Improved by IVF or Embryo Transfer Consistent with Oocyte-Specific Defect. Arian S, Rubin J, Chakchouk I, Sharif M, Mahadevan SK, Erfani H, Shelly K, Liao L, Lorenzo I, Ramakrishnan R, Van den Veyver IB
Reprod Sci (Jul 2021)

Nlrp2 encodes a protein of the oocyte subcortical maternal complex (SCMC), required for embryo development. We previously showed that loss of maternal Nlrp2 in mice causes subfertility, smaller litters with birth defects, and growth abnormalities in offspring, indicating that Nlrp2 is a maternal effect gene and that all embryos from Nlrp2-deficient females that were cultured in vitro arrested before the blastocysts stage. Here, we used time-lapse microscopy to examine the development of cultured embryos from superovulated Nlrp2-deficient and wild-type mice after in vivo and in vitro fertilization. Embryos from Nlrp2-deficient females had similar abnormal cleavage and fragmentation and arrested by blastocyst stage, irrespective of fertilization mode. This indicates that in vitro fertilization does not further perturb or improve the development of cultured embryos. We also transferred embryos from superovulated Nlrp2-deficient and wild-type females to wild-type recipients to investigate if the abnormal reproductive outcomes of Nlrp2-deficient females are primarily driven by oocyte dysfunction or if a suboptimal intra-uterine milieu is a necessary factor. Pregnancies with transferred embryos from Nlrp2-deficient females produced smaller litters, stillbirths, and offspring with birth defects and growth abnormalities. This indicates that the reproductive phenotype is oocyte-specific and is not rescued by development in a wild-type uterus. We further found abnormal DNA methylation at two maternally imprinted loci in the kidney of surviving young adult offspring, confirming persistent DNA methylation disturbances in surviving offspring. These findings have implications for fertility treatments for women with mutations in NLRP2 and other genes encoding SCMC proteins.]]> Wed, 31 Dec 1969 19:00:00 EST Dual Fertilization, Intragenomic Conflict, Genome Downsizing, and Angiosperm Dominance. Roy SW
Trends Plant Sci (Jun 2021)

New work suggests 'subgenome dominance' in polyploids may only occur in angiosperms. Subgenome dominance could explain angiosperm-specific genome reduction, with potential implications for angiosperms' global dominance. I suggest that evolution of the endosperm could have selected for the evolution of subgenome dominance, due to increased hybrid/polyploid incompatibilities and/or through direct reciprocal suppression of maternally- and paternally-inherited genomes.]]> Wed, 31 Dec 1969 19:00:00 EST Dietary Sodium Restriction Results in Tissue-Specific Changes in DNA Methylation in Humans. Kidambi S, Pan X, Yang C, Liu P, Roberts ML, Li Y, Wang T, Laud PW, Liu Y, Rubens M, Thomas R, Widlansky ME, Beyer AM, Liu Y, Cowley AW, Kotchen TA, Munyura Y, Moosreiner A, Mattson DL, Liang M
Hypertension (Jun 2021)

Dietary sodium affects blood pressure (BP) and vascular function. Animal studies suggest epigenetic changes (eg, DNA methylation) are involved. We hypothesized that sodium restriction induces methylation changes in T cells and arterioles in humans. Fifty subjects (49% women) were placed on 1200-mg sodium/day diet for 2 weeks. BP and brachial artery flow-mediated dilation were evaluated. Methylation sequencing (pre- and post-diet) was performed on T-cell (n=50) and biopsied arteriolar (n=10) DNA. RNA sequencing was also performed on arterioles (n=11). Over 2 weeks, mean sodium consumption was 946 mg/day. Average BP reductions after low-sodium intake were -8±13/-4±9 mm Hg (<0.001). Flow-mediated dilation improved (5.8±2.9% to 6.8±3.4%; =0.03). T-cell DNA was substantially more methylated than arterioles. The differentially methylated regions (false discovery rate, <0.05) identified in T cells and arterioles after sodium restriction were located in 117 and 71 genes, respectively. Four genes were identified in both T cells and arterioles (=0.009 for the overlap). The dietary effects on methylation in several DNA regions were associated with dietary effects on BP. Several differentially expressed genes in arterioles contained differentially methylated regions at the significance level of <0.05. In addition, 46 genes contained differentially methylated regions in both human and SS/Mcw rat T cells (=0.03 for the overlap). Sodium restriction significantly affected DNA methylation in T cells and arterioles, some of which are associated with BP. Methylation patterns and sodium effects on methylation are largely tissue specific but also have overlaps between tissues and species. These findings may lead to better understanding of dietary sodium interactions with cellular processes and, therefore, novel therapeutic targets.]]> Wed, 31 Dec 1969 19:00:00 EST Omics sciences for systems biology in Alzheimer's disease: State-of-the-art of the evidence. Hampel H, Nisticò R, Seyfried NT, Levey AI, Modeste E, Lemercier P, Baldacci F, Toschi N, Garaci F, Perry G, Emanuele E, Valenzuela PL, Lucia A, Urbani A, Sancesario GM, Mapstone M, Corbo M, Vergallo A, Lista S,  
Ageing Res Rev (Aug 2021)

Alzheimer's disease (AD) is characterized by non-linear, genetic-driven pathophysiological dynamics with high heterogeneity in biological alterations and disease spatial-temporal progression. Human in-vivo and post-mortem studies point out a failure of multi-level biological networks underlying AD pathophysiology, including proteostasis (amyloid-β and tau), synaptic homeostasis, inflammatory and immune responses, lipid and energy metabolism, oxidative stress. Therefore, a holistic, systems-level approach is needed to fully capture AD multi-faceted pathophysiology. Omics sciences - genomics, epigenomics, transcriptomics, proteomics, metabolomics, lipidomics - embedded in the systems biology (SB) theoretical and computational framework can generate explainable readouts describing the entire biological continuum of a disease. Such path in Neurology is encouraged by the promising results of omics sciences and SB approaches in Oncology, where stage-driven pathway-based therapies have been developed in line with the precision medicine paradigm. Multi-omics data integrated in SB network approaches will help detect and chart AD upstream pathomechanistic alterations and downstream molecular effects occurring in preclinical stages. Finally, integrating omics and neuroimaging data - i.e., neuroimaging-omics - will identify multi-dimensional biological signatures essential to track the clinical-biological trajectories, at the subpopulation or even individual level.]]> Wed, 31 Dec 1969 19:00:00 EST Association between PEG3 DNA methylation and high-grade cervical intraepithelial neoplasia. Bosire C, Vidal AC, Smith JS, Jima D, Huang Z, Skaar D, Valea F, Bentley R, Gradison M, Yarnall KSH, Ford A, Overcash F, Murphy SK, Hoyo C
Infect Agent Cancer (Jun 2021)

Epigenetic mechanisms are hypothesized to contribute substantially to the progression of cervical intraepithelial neoplasia (CIN) to cervical cancer, although empirical data are limited.]]> Wed, 31 Dec 1969 19:00:00 EST DevOmics: an integrated multi-omics database of human and mouse early embryo. Yan Z, An J, Peng Y, Kong S, Liu Q, Yang M, He Q, Song S, Chen Y, Chen W, Li R, Qiao J, Yan L
Brief Bioinform (Jun 2021)

Transcriptomic and epigenetic alterations during early embryo development have been proven to play essential roles in regulating the cell fate. Nowadays, advances in single-cell transcriptomics and epigenomics profiling techniques provide large volumes of data for understanding the molecular regulatory mechanisms in early embryos and facilitate the investigation of assisted reproductive technology as well as preimplantation genetic testing. However, the lack of integrated data collection and unified analytic procedures greatly limits their usage in scientific research and clinical application. Hence, it is necessary to establish a database integrating the regulatory information of human and mouse early embryos with unified analytic procedures. Here, we introduce DevOmics (http://devomics.cn/), which contains normalized gene expression, DNA methylation, histone modifications (H3K4me3, H3K9me3, H3K27me3, H3K27ac), chromatin accessibility and 3D chromatin architecture profiles of human and mouse early embryos spanning six developmental stages (zygote, 2cell, 4cell, 8cell, morula and blastocyst (ICM, TE)). The current version of DevOmics provides Search and Advanced Search for retrieving genes a researcher is interested in, Analysis Tools including the differentially expressed genes (DEGs) analysis for acquiring DEGs between different types of samples, allelic explorer for displaying allele-specific gene expression as well as epigenetic modifications and correlation analysis for showing the dynamic changes in different layers of data across developmental stages, as well as Genome Browser and Ortholog for visualization. DevOmics offers a user-friendly website for biologists and clinicians to decipher molecular regulatory mechanisms of human and mouse early embryos.]]> Wed, 31 Dec 1969 19:00:00 EST Epigenomics in the single cell era, an important read out for genome function and cell identity. Pinheiro I, Torres-Padilla ME, Almouzni G
Epigenomics (Jun 2021)

]]> Wed, 31 Dec 1969 19:00:00 EST How does epigenetics influence the course of evolution? Ashe A, Colot V, Oldroyd BP
Philos Trans R Soc Lond B Biol Sci (Jun 2021)

Epigenetics is the study of changes in gene activity that can be transmitted through cell divisions but cannot be explained by changes in the DNA sequence. Epigenetic mechanisms are central to gene regulation, phenotypic plasticity, development and the preservation of genome integrity. Epigenetic mechanisms are often held to make a minor contribution to evolutionary change because epigenetic states are typically erased and reset at every generation, and are therefore, not heritable. Nonetheless, there is growing appreciation that epigenetic variation makes direct and indirect contributions to evolutionary processes. First, some epigenetic states are transmitted intergenerationally and affect the phenotype of offspring. Moreover, heritable 'epialleles' exist and are quite common in plants. Such epialleles could, therefore, be subject to natural selection in the same way as conventional DNA sequence-based alleles. Second, epigenetic variation enhances phenotypic plasticity and phenotypic variance and thus can modulate the effect of natural selection on sequence-based genetic variation. Third, given that phenotypic plasticity is central to the adaptability of organisms, epigenetic mechanisms that generate plasticity and acclimation are important to consider in evolutionary theory. Fourth, some genes are under selection to be 'imprinted' identifying the sex of the parent from which they were derived, leading to parent-of-origin-dependent gene expression and effects. These effects can generate hybrid disfunction and contribute to speciation. Finally, epigenetic processes, particularly DNA methylation, contribute directly to DNA sequence evolution, because they act as mutagens on the one hand and modulate genome stability on the other by keeping transposable elements in check. This article is part of the theme issue 'How does epigenetics influence the course of evolution?']]> Wed, 31 Dec 1969 19:00:00 EST Therapies in preclinical and clinical development for Angelman syndrome. Markati T, Duis J, Servais L
Expert Opin Investig Drugs (Jun 2021)

Angelman syndrome is a rare genetic neurodevelopmental disorder, caused by deficiency or abnormal function of the maternal ubiquitin protein-ligase E3A, known as UBE3A, in the central nervous system. Currently, there is no disease-modifying treatment available, but the therapeutic pipeline of Angelman syndrome includes at least 15 mechanistically different approaches at preclinical or clinical development. In the coming years, several clinical trials will be enrolling patients and, therefore, Angelman syndrome community needs to be aware of all options.]]> Wed, 31 Dec 1969 19:00:00 EST Parent-of-origin effects, allele-specific expression, genomic imprinting and paternal manipulation in social insects. Oldroyd BP, Yagound B
Philos Trans R Soc Lond B Biol Sci (Jun 2021)

Haplo-diploidy and the relatedness asymmetries it generates mean that social insects are prime candidates for the evolution of genomic imprinting. In single-mating social insect species, some genes may be selected to evolve genomic mechanisms that enhance reproduction by workers when they are inherited from a female. This situation reverses in multiple mating species, where genes inherited from fathers can be under selection to enhance the reproductive success of daughters. Reciprocal crosses between subspecies of honeybees have shown strong parent-of-origin effects on worker reproductive phenotypes, and this could be evidence of such genomic imprinting affecting genes related to worker reproduction. It is also possible that social insect fathers directly affect gene expression in their daughters, for example, by placing small interfering RNA molecules in semen. Gene expression studies have repeatedly found evidence of parent-specific gene expression in social insects, but it is unclear at this time whether this arises from genomic imprinting, paternal manipulation, an artefact of cyto-nuclear interactions, or all of these. This article is part of the theme issue 'How does epigenetics influence the course of evolution?']]> Wed, 31 Dec 1969 19:00:00 EST Lack of parent-of-origin effects in Nasonia jewel wasp: A replication and extension study. Olney KC, Gibson JD, Natri HM, Underwood A, Gadau J, Wilson MA
PLoS One (2021)

In diploid cells, the paternal and maternal alleles are, on average, equally expressed. There are exceptions from this: a small number of genes express the maternal or paternal allele copy exclusively. This phenomenon, known as genomic imprinting, is common among eutherian mammals and some plant species; however, genomic imprinting in species with haplodiploid sex determination is not well characterized. Previous work reported no parent-of-origin effects in the hybrids of closely related haplodiploid Nasonia vitripennis and Nasonia giraulti jewel wasps, suggesting a lack of epigenetic reprogramming during embryogenesis in these species. Here, we replicate the gene expression dataset and observations using different individuals and sequencing technology, as well as reproduce these findings using the previously published RNA sequence data following our data analysis strategy. The major difference from the previous dataset is that they used an introgression strain as one of the parents and we found several loci that resisted introgression in that strain. Our results from both datasets demonstrate a species-of-origin effect, rather than a parent-of-origin effect. We present a reproducible workflow that others may use for replicating the results. Overall, we reproduced the original report of no parent-of-origin effects in the haplodiploid Nasonia using the original data with our new processing and analysis pipeline and replicated these results with our newly generated data.]]> Wed, 31 Dec 1969 19:00:00 EST Chromatin accessibility changes at intergenic regions are associated with ovarian cancer drug resistance. Gallon J, Loomis E, Curry E, Martin N, Brody L, Garner I, Brown R, Flanagan JM
Clin Epigenetics (Jun 2021)

Resistance to DNA damaging chemotherapies leads to cancer treatment failure and poor patient prognosis. We investigated how genomic distribution of accessible chromatin sites is altered during acquisition of cisplatin resistance using matched ovarian cell lines from high grade serous ovarian cancer (HGSOC) patients before and after becoming clinically resistant to platinum-based chemotherapy.]]> Wed, 31 Dec 1969 19:00:00 EST Applications of single-cell sequencing in cancer research: progress and perspectives. Lei Y, Tang R, Xu J, Wang W, Zhang B, Liu J, Yu X, Shi S
J Hematol Oncol (Jun 2021)

Single-cell sequencing, including genomics, transcriptomics, epigenomics, proteomics and metabolomics sequencing, is a powerful tool to decipher the cellular and molecular landscape at a single-cell resolution, unlike bulk sequencing, which provides averaged data. The use of single-cell sequencing in cancer research has revolutionized our understanding of the biological characteristics and dynamics within cancer lesions. In this review, we summarize emerging single-cell sequencing technologies and recent cancer research progress obtained by single-cell sequencing, including information related to the landscapes of malignant cells and immune cells, tumor heterogeneity, circulating tumor cells and the underlying mechanisms of tumor biological behaviors. Overall, the prospects of single-cell sequencing in facilitating diagnosis, targeted therapy and prognostic prediction among a spectrum of tumors are bright. In the near future, advances in single-cell sequencing will undoubtedly improve our understanding of the biological characteristics of tumors and highlight potential precise therapeutic targets for patients.]]> Wed, 31 Dec 1969 19:00:00 EST Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature. Rots D, Chater-Diehl E, Dingemans AJM, Goodman SJ, Siu MT, Cytrynbaum C, Choufani S, Hoang N, Walker S, Awamleh Z, Charkow J, Meyn S, Pfundt R, Rinne T, Gardeitchik T, de Vries BBA, Deden AC, Leenders E, Kwint M, Stumpel CTRM, Stevens SJC, Vermeulen JR, van Harssel JVT, Bosch DGM, van Gassen KLI, van Binsbergen E, de Geus CM, Brackel H, Hempel M, Lessel D, Denecke J, Slavotinek A, Strober J, Crunk A, Folk L, Wentzensen IM, Yang H, Zou F, Millan F, Person R, Xie Y, Liu S, Ousager LB, Larsen M, Schultz-Rogers L, Morava E, Klee EW, Berry IR, Campbell J, Lindstrom K, Pruniski B, Neumeyer AM, Radley JA, Phornphutkul C, Schmidt B, Wilson WG, Õunap K, Reinson K, Pajusalu S, van Haeringen A, Ruivenkamp C, Cuperus R, Santos-Simarro F, Palomares-Bralo M, Pacio-Míguez M, Ritter A, Bhoj E, Tønne E, Tveten K, Cappuccio G, Brunetti-Pierri N, Rowe L, Bunn J, Saenz M, Platzer K, Mertens M, Caluseriu O, Nowaczyk MJM, Cohn RD, Kannu P, Alkhunaizi E, Chitayat D, Scherer SW, Brunner HG, Vissers LELM, Kleefstra T, Koolen DA, Weksberg R
Am J Hum Genet (Jun 2021)

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.]]> Wed, 31 Dec 1969 19:00:00 EST