Congenital hearing loss affects one in 500 newborns. Sequence variations in OTOF, which encodes the calcium-binding protein otoferlin, are responsible for 1-8% of congenital, nonsyndromic hearing loss and are the leading cause of auditory neuropathy spectrum disorders. The natural history of otoferlin-related hearing loss, the relationship between OTOF genotype and hearing loss phenotype, and the outcomes of clinical practices in patients with this genetic disorder are incompletely understood because most analyses have reported on small numbers of cases with homogeneous OTOF genotypes. Here, we present the first systematic, quantitative literature review of otoferlin-related hearing loss, which analyzes patient-specific data from 422 individuals across 61 publications. While most patients display a typical phenotype of severe-to-profound hearing loss with prelingual onset, 10-15% of patients display atypical phenotypes, including mild-to-moderate, progressive, and temperature-sensitive hearing loss. Patients' phenotypic presentations appear to depend on their specific genotypes. For example, non-truncating variants located in and immediately downstream of the C2E calcium-binding domain are more likely to produce atypical phenotypes. Additionally, the prevalence of certain sequence variants and their associated phenotypes varies between populations due to evolutionary founder effects. Our analyses also suggest otoacoustic emissions are less common in older patients and those with two truncating OTOF variants. Critically, our review has implications for the application and limitations of clinical practices, including newborn hearing screenings, hearing aid trials, cochlear implants, and upcoming gene therapy clinical trials. We conclude by discussing the limitations of available research and recommendations for future studies on this genetic cause of hearing loss.

As one of the most common structural birth defects, orofacial clefts (OFCs) have been studied for decades, and recent studies have demonstrated that there are genetic differences between the different phenotypic presentations of OFCs. However, the contribution of rare genetic variation genome-wide to different subtypes of OFCs has been understudied, with most studies focusing on common genetic variation or rare variation within targeted regions of the genome. Therefore, we used whole-genome sequencing data from the Gabriella Miller Kids First Pediatric Research Program to conduct a gene-based burden analysis to test for genetic modifiers of cleft lip (CL) vs cleft lip and palate (CLP). We found that there was a significantly increased burden of rare variants in SEC24D in CL cases compared to CLP cases (p = 6.86 [Formula: see text] 10-7). Of the 15 variants within SEC24D, 53.3% were synonymous, but overlapped a known craniofacial enhancer. We then tested whether these variants could alter predicted transcription factor binding sites (TFBS), and found that the rare alleles destroyed binding sites for 9 transcription factors (TFs), including Pax1 (p = 0.0009), and created binding sites for 23 TFs, including Pax6 (p = 6.12 [Formula: see text] 10-5) and Pax9 (p = 0.0001), which are known to be involved in normal craniofacial development, suggesting a potential mechanism by which these synonymous variants could have a functional impact. Overall, this study indicates that rare genetic variation may contribute to the phenotypic heterogeneity of OFCs and suggests that regulatory variation may also contribute and warrant further investigation in future studies of genetic variants controlling risk to OFC.

There has been considerable recent interest in the role that germline variants in histone genes play in Mendelian syndromes. Specifically, missense variants in H3-3A and H3-3B, which both encode Histone 3.3, were discovered to cause a novel neurodevelopmental disorder, Bryant-Li-Bhoj syndrome. Most of the causative variants are private and scattered throughout the protein, but all seem to have either a gain-of-function or dominant negative effect on protein function. This is highly unusual and not well understood. However, there is extensive literature about the effects of Histone 3.3 mutations in model organisms. Here, we collate the previous data to provide insight into the elusive pathogenesis of missense variants in Histone 3.3.

The multidisciplinary Epigenetics and Chromatin Clinic at Johns Hopkins provides comprehensive medical care for individuals with rare disorders that involve disrupted epigenetics. Initially centered on classical imprinting disorders, the focus shifted to the rapidly emerging group of genetic disorders resulting from pathogenic germline variants in epigenetic machinery genes. These are collectively called the Mendelian disorders of the epigenetic machinery (MDEMs), or more broadly, Chromatinopathies. In five years, 741 clinic visits have been completed for 432 individual patients, with 153 having confirmed epigenetic diagnoses. Of these, 115 individuals have one of 26 MDEMs with every single one exhibiting global developmental delay and/or intellectual disability. This supports prior observations that intellectual disability is the most common phenotypic feature of MDEMs. Additional common phenotypes in our clinic include growth abnormalities and neurodevelopmental issues, particularly hypotonia, attention-deficit/hyperactivity disorder (ADHD), and anxiety, with seizures and autism being less common. Overall, our patient population is representative of the broader group of MDEMs and includes mostly autosomal dominant disorders impacting writers more so than erasers, readers, and remodelers of chromatin marks. There is an increased representation of dual function components with a reader and an enzymatic domain. As expected, diagnoses were made mostly by sequencing but were aided in some cases by DNA methylation profiling. Our clinic has helped to facilitate the discovery of two new disorders, and our providers are actively developing and implementing novel therapeutic strategies for MDEMs. These data and our high follow-up rate of over 60% suggest that we are achieving our mission to diagnose, learn from, and provide optimal care for our patients with disrupted epigenetics.

Nuclear speckles are small, membrane-less organelles that reside within the nucleus. Nuclear speckles serve as a regulatory hub coordinating complex RNA metabolism steps including gene transcription, pre-mRNA splicing, RNA modifications, and mRNA nuclear export. Reflecting the importance of proper nuclear speckle function in regulating normal human development, an increasing number of genetic disorders have been found to result from mutations in the genes encoding nuclear speckle proteins. To denote this growing class of genetic disorders, we propose "nuclear speckleopathies". Notably, developmental disabilities are commonly seen in individuals with nuclear speckleopathies, suggesting the particular importance of nuclear speckles in ensuring normal neurocognitive development. In this review article, a general overview of nuclear speckle function, and the current knowledge of the mechanisms underlying some nuclear speckleopathies, such as ZTTK syndrome, NKAP-related syndrome, TARP syndrome, and TAR syndrome, are discussed. These nuclear speckleopathies represent valuable models to understand the basic function of nuclear speckles and how its functional defects result in human developmental disorders.

Non-coding RNAs (ncRNAs) are emerging as biomarkers, molecular signatures, and therapeutic tools and targets for diseases. In this review, we focus specifically on skin diseases to highlight how two classes of ncRNAs-microRNAs and long noncoding RNAs-are being used to diagnose medical conditions of unclear etiology, improve our ability to guide treatment response, and predict disease prognosis. Furthermore, we explore how ncRNAs are being used as both as drug targets and associated therapies have unique benefits, risks, and challenges to development, but offer a distinctive promise for improving patient care and outcomes.

Pathogenic variants in genes that encode epigenetic regulators are the cause for more than 100 rare neurodevelopmental syndromes also termed "chromatinopathies". DNA methylation signatures, syndrome-specific patterns of DNA methylation alterations, serve as both a research avenue for elucidating disease pathophysiology and a clinical diagnostic tool. The latter is well established, especially for the classification of variants of uncertain significance (VUS). In this perspective, we describe the seminal DNA methylation signature research in chromatinopathies; the complex relationships between genotype, phenotype and DNA methylation, and the future applications of DNA methylation signatures.

The OMICs cascade describes the hierarchical flow of information through biological systems. The epigenome sits at the apex of the cascade, thereby regulating the RNA and protein expression of the human genome and governs cellular identity and function. Genes that regulate the epigenome, termed epigenes, orchestrate complex biological signaling programs that drive human development. The broad expression patterns of epigenes during human development mean that pathogenic germline mutations in epigenes can lead to clinically significant multi-system malformations, developmental delay, intellectual disabilities, and stem cell dysfunction. In this review, we refer to germline developmental disorders caused by epigene mutation as "chromatinopathies". We curated the largest number of human chromatinopathies to date and our expanded approach more than doubled the number of established chromatinopathies to 179 disorders caused by 148 epigenes. Our study revealed that 20.6% (148/720) of epigenes cause at least one chromatinopathy. In this review, we highlight key examples in which OMICs approaches have been applied to chromatinopathy patient biospecimens to identify underlying disease pathogenesis. The rapidly evolving OMICs technologies that couple molecular biology with high-throughput sequencing or proteomics allow us to dissect out the causal mechanisms driving temporal-, cellular-, and tissue-specific expression. Using the full repertoire of data generated by the OMICs cascade to study chromatinopathies will provide invaluable insight into the developmental impact of these epigenes and point toward future precision targets for these rare disorders.

Metazoan development arises from spatiotemporal control of gene expression, which depends on epigenetic regulators like the polycomb group proteins (PcG) that govern the chromatin landscape. PcG proteins facilitate the addition and removal of histone 2A monoubiquitination at lysine 119 (H2AK119ub1), which regulates gene expression, cell fate decisions, cell cycle progression, and DNA damage repair. Regulation of these processes by PcG proteins is necessary for proper development, as pathogenic variants in these genes are increasingly recognized to underly developmental disorders. Overlapping features of developmental syndromes associated with pathogenic variants in specific PcG genes suggest disruption of central developmental mechanisms; however, unique clinical features observed in each syndrome suggest additional non-redundant functions for each PcG gene. In this review, we describe the clinical manifestations of pathogenic PcG gene variants, review what is known about the molecular functions of these gene products during development, and interpret the clinical data to summarize the current evidence toward an understanding of the genetic and molecular mechanism.

BACKGROUND: It is unclear whether gut microbiota (GM) affects the risk of optic neuritis (ON) through the "gut-brain" axis and the "gut-retina" axis. To examine the causal relationship between GM and ON, we conducted Mendelian randomization (MR) study. METHODS: Up to 18,340 samples of 24 population-based cohorts were included in genome-wide association study (GWAS) of 196 GM taxa. ON outcomes were selected from the FinnGen GWAS (951 ON cases and 307,092 controls). In addition, the GWAS based on UK Biobank (UKB) (105 ON cases and 456,243 controls) was used for further exploration. Inverse variance weighted (IVW) was carried out to estimate their effects on ON risk and the MR assumptions were evaluated in sensitivity analyses. RESULTS: Among the 196 GM taxa, the IVW results confirmed that Family -Peptococcaceae (P = 2.17 × 10-3), Genus- Hungatella (P = 4.57 × 10-3) and genus-Eubacterium_rectale_group (P = 0.02) were correlated with the risk of ON based on Finngen GWAS. Based on data from UKB, Genus- Eubacterium_hallii_group (P = 1.50 × 10-3) and Genus- Ruminococcaceae_UCG_002 (P = 0.02) were correlated with the risk of ON. At the phylum, class and order levels, no GM taxa were causally related to ON (P > 0.05). Heterogeneity (P > 0.05) and pleiotropy (P > 0.05) analysis confirmed the robustness of the MR results. CONCLUSION: Our MR findings support the causal effect of specific GM taxa on ON. GM may affect the risk of ON through the "gut-brain" axis and the "gut-retina" axis. However, further research is needed to confirm the relevant mechanism of the relationship between GM and ON.

Advancing age is a major risk factor of Alzheimer's disease (AD). The worldwide prevalence of AD is approximately 50 million people, and this number is projected to increase substantially. The molecular mechanisms underlying the aging-associated susceptibility to cognitive impairment in AD are largely unknown. As a hallmark of aging, cellular senescence is a significant contributor to aging and age-related diseases including AD. Senescent neurons and glial cells have been detected to accumulate in the brains of AD patients and mouse models. Importantly, selective elimination of senescent cells ameliorates amyloid beta and tau pathologies and improves cognition in AD mouse models, indicating a critical role of cellular senescence in AD pathogenesis. Nonetheless, the mechanisms underlying when and how cellular senescence contributes to AD pathogenesis remain unclear. This review provides an overview of cellular senescence and discusses recent advances in the understanding of the impact of cellular senescence on AD pathogenesis, with brief discussions of the possible role of cellular senescence in other neurodegenerative diseases including Down syndrome, Parkinson's disease, multiple sclerosis, and amyotrophic lateral sclerosis.

Inflammatory bowel disease (IBD), with Crohn's disease and ulcerative colitis as main subtypes, is a prototypical multifactorial disease with both genetic and environmental factors involved. Genetically, IBD covers a wide spectrum from monogenic to polygenic forms. In polygenic disease, many genetic variants each contribute a small amount to disease risk. With the advent of genome-wide association studies (GWAS), it became possible to find these variants and corresponding genes, leading so far to the discovery of ca 240 loci associated with IBD. Together, these however explain only 20-25% of the heritability of IBD, leaving a large portion unaccounted for. This missing heritability might be hidden in common variants with even lower effect than the ones currently found through GWAS, but also in rare variants which can be found through large-scale sequencing studies or potentially in multiplex families. In this review, we will give an overview of the current knowledge about the genetics of non-monogenic IBD and how it differs from the monogenic form(s), and future perspectives. The history of IBD genetic studies from twin studies over linkage studies to GWAS, and finally large-scale sequencing studies and the revisiting of multiplex families will be discussed.

Pain often occurs in parallel with neuropsychiatric disorders. However, the underlying mechanisms and potential causality have not been well studied. We collected the genome-wide association study (GWAS) summary statistics of 26 common pain and neuropsychiatric disorders with sample size ranging from 17,310 to 482,730 in European population. The genetic correlation between pair of pain and neuropsychiatric disorders, as well as the relevant cell types were investigated by linkage disequilibrium (LD) score regression analyses. Then, transcriptome-wide association study (TWAS) was applied to identify the potential shared genes by integrating the gene expression information and GWAS. In addition, Mendelian randomization (MR) analyses were conducted to infer the potential causality between pain and neuropsychiatric disorders. Among the 169 pairwise pain and neuropsychiatric disorders, 55 pairs showed positive correlations (median rg = 0.43) and 9 pairs showed negative correlations (median rg =  -0.31). Using MR analyses, 26 likely causal associations were identified, including that neuroticism and insomnia were risk factors for most of short-term pain, and multisite chronic pain was risk factor for neuroticism, insomnia, major depressive disorder and attention deficit/hyperactivity disorder, and vice versa. The signals of pain and neuropsychiatric disorders tended to be enriched in the functional regions of cell types from central nervous system (CNS). A total of 19 genes shared in at least one pain and neuropsychiatric disorder pair were identified by TWAS, including AMT, NCOA6, and UNC45A, which involved in glycine degradation, insulin secretion, and cell proliferation, respectively. Our findings provided the evidence of shared genetic structure, causality and potential shared pathogenic mechanisms between pain and neuropsychiatric disorders, and enhanced our understanding of the comorbidities of pain and neuropsychiatric disorders.

Exocytosis is the process by which secretory vesicles fuse with the plasma membrane to deliver materials to the cell surface or to release cargoes to the extracellular space. The exocyst-an evolutionarily conserved octameric protein complex-mediates spatiotemporal control of SNARE complex assembly for vesicle fusion and tethering the secretory vesicles to the plasma membrane. The exocyst participates in diverse cellular functions, including protein trafficking to the plasma membrane, membrane extension, cell polarity, neurite outgrowth, ciliogenesis, cytokinesis, cell migration, autophagy, host defense, and tumorigenesis. Exocyst subunits are essential for cell viability; and mutations or variants in several exocyst subunits have been implicated in human diseases, mostly neurodevelopmental disorders and ciliopathies. These conditions often share common features such as developmental delay, intellectual disability, and brain abnormalities. In this review, we summarize the mutations and variants in exocyst subunits that have been linked to disease and discuss the implications of exocyst dysfunction in other disorders.

Regulatory elements are the genomic regions that interact with transcription factors to control cell-type-specific gene expression in different cellular environments. A precise and complete catalog of functional elements encoded by the human genome is key to understanding mammalian gene regulation. Here, we review the current state of regulatory element annotation. We first provide an overview of assays for characterizing functional elements, including genome, epigenome, transcriptome, three-dimensional chromatin interaction, and functional validation assays. We then discuss computational methods for defining regulatory elements, including peak-calling and other statistical modeling methods. Finally, we introduce several high-quality lists of regulatory element annotations and suggest potential future directions.

Monogenic intestinal epithelial disorders, also known as congenital diarrheas and enteropathies (CoDEs), are a group of rare diseases that result from mutations in genes that primarily affect intestinal epithelial cell function. Patients with CoDE disorders generally present with infantile-onset diarrhea and poor growth, and often require intensive fluid and nutritional management. CoDE disorders can be classified into several categories that relate to broad areas of epithelial function, structure, and development. The advent of accessible and low-cost genetic sequencing has accelerated discovery in the field with over 45 different genes now associated with CoDE disorders. Despite this increasing knowledge in the causal genetics of disease, the underlying cellular pathophysiology remains incompletely understood for many disorders. Consequently, clinical management options for CoDE disorders are currently limited and there is an urgent need for new and disorder-specific therapies. In this review, we provide a general overview of CoDE disorders, including a historical perspective of the field and relationship to other monogenic disorders of the intestine. We describe the genetics, clinical presentation, and known pathophysiology for specific disorders. Lastly, we describe the major challenges relating to CoDE disorders, briefly outline key areas that need further study, and provide a perspective on the future genetic and therapeutic landscape.

Although COVID-19 is mostly a pulmonary disease, it is now well accepted that it can cause a much broader spectrum of signs and symptoms and affect many other organs and tissue. From mild anosmia to severe ischemic stroke, the impact of SARS-CoV-2 on the central nervous system is still a great challenge to scientists and health care practitioners. Besides the acute and severe neurological problems described, as encephalopathies, leptomeningitis, and stroke, after 2 years of pandemic, the chronic impact observed during long-COVID or the post-acute sequelae of COVID-19 (PASC) greatly intrigues scientists worldwide. Strikingly, even asymptomatic, and mild diseased patients may evolve with important neurological and psychiatric symptoms, as confusion, memory loss, cognitive decline, chronic fatigue, associated or not with anxiety and depression. Thus, the knowledge on the correlation between COVID-19 and the central nervous system is of great relevance. In this sense, here we discuss some important mechanisms obtained from in vitro and in vivo investigation regarding how SARS-CoV-2 impacts the brain and its cells and function.

Diarrhoeal disorders in childhood extend beyond the inflammatory bowel diseases. Persistent and severe forms of diarrhoea can occur from birth and are associated with significant morbidity and mortality. These disorders can affect not only the gastrointestinal tract but frequently have extraintestinal manifestations, immunodeficiencies and endocrinopathies. Genomic analysis has advanced our understanding of these conditions and has revealed precision-based treatment options such as potentially curative haematopoietic stem cell transplant. Although many new mutations have been discovered, there is frequently no clear genotype-phenotype correlation. The functional effects of gene mutations can be studied in model systems such as patient-derived organoids. This allows us to further characterise these disorders and advance our understanding of the pathophysiology of the intestinal mucosa. In this review, we will provide an up to date overview of genes involved in diarrhoeal disorders of early onset, particularly focussing on the more recently described gene defects associated with protein loosing enteropathy.

Aging is a progressive multifaceted functional decline of a biological system. Chronic age-related conditions such as neurodegenerative diseases are leading causes of death worldwide, and they are becoming a pressing problem for our society. To address this global challenge, there is a need for novel, safe, and effective rejuvenation therapies aimed at reversing age-related phenotypes and improving human health. With gene expression being a key determinant of cell identity and function, and in light of recent studies reporting rejuvenation effects through genetic perturbations, we propose an age reversal strategy focused on reprogramming the cell transcriptome to a youthful state. To this end, we suggest using transcriptomic data from primary human cells to predict rejuvenation targets and develop high-throughput aging assays, which can be used in large perturbation screens. We propose neural cells as particularly relevant targets for rejuvenation due to substantial impact of neurodegeneration on human frailty. Of all cell types in the brain, we argue that glutamatergic neurons, neuronal stem cells, and oligodendrocytes represent the most impactful and tractable targets. Lastly, we provide experimental designs for anti-aging reprogramming screens that will likely enable the development of neuronal age reversal therapies, which hold promise for dramatically improving human health.

For several years, experts have warned about the lack of diversity in genetic research databases, and researchers have devoted time and resources to recruiting subjects from underrepresented subgroups. In this study, we review published reports in academic journals of genetic studies of Alzheimer's disease to note whether demographic diversity was indicated in the reports and, if so, the extent of representation of non-European subjects over the period from 1997 to 2022. We use multivariate regression analysis to analyze changes over time and to explain variation across studies. Our analysis indicates that reported diversity has not changed over time. Rather, it appears to have remained relatively constant, since Genome-Wide Association Studies (GWASs) were first used in the 1990s. We find most variation to be across journals rather than within journals, suggesting that characteristics of journals are an important influence on the dissemination of research with diverse samples. Lack of racial diversity in genetic databases used to develop clinical applications could lead to disparities in the effectiveness of those applications for underrepresented groups.