Genome-sequence-based newborn screening (gNBS) has substantial potential to improve outcomes in hundreds of severe childhood genetic disorders (SCGDs). However, a major impediment to gNBS is imprecision due to variants classified as pathogenic (P) or likely pathogenic (LP) that are not SCGD causal. gNBS with 53,855 P/LP variants, 342 genes, 412 SCGDs, and 1,603 therapies was positive in 74% of UK Biobank

Large prospective clinical trials are underway or planned that examine the clinical utility and cost effectiveness of genome-based newborn screening (gNBS). One gNBS platform, BeginNGS, currently screens 53,575 variants for 412 severe childhood genetic diseases with 1,603 efficacious therapies. Retrospective evaluation of BeginNGS in 618,290 subjects suggests adequate sensitivity and positive predictive

Increasing evidence is emerging to link age-associated complex musculoskeletal diseases, including osteoarthritis (OA), to developmental factors. Multiple studies have shown a functional role for DNA methylation in the genetic mechanisms of OA risk using articular cartilage samples taken from aged individuals, yet knowledge of temporal changes to the methylome during human cartilage development is

Translational efforts in osteoarthritis are hampered by a gap in our understanding of disease processes at the molecular level. Here, we present evidence of pronounced transcriptional changes in high- and low-disease-grade cartilage tissue, pointing to embryonic processes involved in disease progression. We identify shared transcriptional programs between osteoarthritis cartilage and cell populations

Analysis of exome data from the latest release of the Genome Aggregation Database (gnomAD v.4.1.0) revealed a significant carrier burden of pathogenic/likely pathogenic (P/LP) variants in genes associated with autosomal-recessive conditions across diverse ancestral populations. Carrier screening panels are routinely offered to reproductive partners to inform their risk of having an affected child.

Female infertility is a common and complex health problem affecting millions of women worldwide. While multiple factors can contribute to this condition, the underlying cause remains elusive in up to 15%–30% of affected individuals. In our large genome-wide association study (GWAS) of 22,849 women with infertility and 198,989 control individuals from the Finnish population cohort FinnGen, we unveil

Underrepresentation in clinical genomics research limits the generalizability of findings and the benefits of scientific discoveries. We describe the impact of patient-centered, data-driven recruitment and retention strategies in a pediatric genome sequencing study. We collaborated with a stakeholder board, conducted formative research with adults whose children had undergone genomic testing, and piloted

By improving disease risk prediction, polygenic risk scores (PRSs) could have a significant impact on health promotion and disease prevention. Due to the historical oversampling of populations with European ancestry for genome-wide association studies, PRSs perform less well in other, understudied populations, leading to concerns that clinical use in their current forms could widen health care disparities

There has been considerable progress in building models to predict the effect of missense substitutions in protein-coding genes, fueled in large part by progress in applying deep learning methods to sequence data. These models have the potential to enable clinical variant annotation on a large scale and hence increase the impact of patient sequencing in guiding diagnosis and treatment. To realize this

Secondary structures are non-canonical arrangements of nucleic acids due to intra-strand interactions, including base pairing, stacking, or other higher-order features that deviate from the standard double-helical conformation. While these structures are extensively studied in RNA, they can also form when DNA becomes single stranded, creating topological roadblocks that can impact essential DNA-based

Individuals with obesity caused by biallelic pathogenic LEPR (leptin receptor) variants can benefit from setmelanotide, the novel MC4R agonist. An ongoing phase 3 clinical trial (NCT05093634) includes individuals with obesity who carry a heterozygous LEPR variant, although the obesogenic impact of these variants remains incompletely evaluated. The aim of this study was to functionally assess heterozygous

We introduce a sizable (n = 34) whole-genome dataset on Armenians, a population inhabiting the region in West Asia known as the Armenian highlands. Equipped with this genetic data, we conducted a whole-genome study of Armenians and deciphered their fine-scale population structure and complex demographic history. We demonstrated that the Armenian populations from western, central, and eastern parts

Population-level genetic studies are overwhelmingly biased toward European ancestries. Transferring genetic predictions from European ancestries to other ancestries results in a substantial loss of accuracy. Yet, it remains unclear how much various genetic factors, such as causal effect differences, linkage disequilibrium (LD) differences, or allele frequency differences, contribute to the loss of

Local genetic correlation analysis is an important tool for identifying genetic loci with shared biology across traits. Recently, Border et al. have shown that the results of these analyses are confounded by cross-trait assortative mating (xAM), leading to many false-positive findings. Here, we describe LAVA-Knock, a local genetic correlation method that builds off an existing genetic correlation method

Polycystic ovarian syndrome (PCOS) is an endocrine syndrome that affects a large portion of women worldwide. This proteogenomic and functional study aimed to uncover candidate therapeutic targets for PCOS. We comprehensively investigated the causal association between circulating proteins and PCOS using two-sample Mendelian randomization analysis. Cis-protein quantitative trait loci were derived from

Delineation of structural variants (SVs) at sequence resolution in highly repetitive genomic regions has long been intractable. The sequence properties, origins, and functional effects of classes of genomic rearrangements such as ring chromosomes and Robertsonian translocations thus remain unknown. To resolve these complex structures, we leveraged several recent milestones in the field, including (1)

Mechanisms of abdominal obesity GWAS variants have remained largely unknown. To elucidate these mechanisms, we leveraged subcutaneous adipose tissue (SAT) single nucleus RNA-sequencing and genomics data. After discovering that heritability of abdominal obesity is enriched in adipocytes, we focused on a SAT unique adipocyte marker gene, the transcription factor TBX15, and its abdominal obesity-associated

The search for prognostic biomarkers capable of predicting patient outcomes, by analyzing gene expression in tissue samples and other molecular profiles, remains largely focused on single-gene-based or global-gene-search approaches. Gene-centric approaches, while foundational, fail to capture the higher-order dependencies that reflect the activities of co-regulated processes, pathway alterations, and

Normal tissues adjacent to the tumor (NATs) may harbor early breast carcinogenesis events driven by field cancerization. Although previous studies have characterized copy-number (CN) and transcriptomic alterations, the evolutionary history of NATs in breast cancer (BC) remains poorly characterized. Utilizing whole-genome sequencing (WGS), methylation profiling, and RNA sequencing (RNA-seq), we analyzed

Four main medulloblastoma (MB) molecular subtypes have been identified based on transcriptional, DNA methylation, and genetic profiles. However, it is currently not known whether 3D genome architecture differs between MB subtypes. To address this question, we performed in situ Hi-C to reconstruct the 3D genome architecture of MB subtypes. In total, we generated Hi-C and matching transcriptome data

WD repeat domain 83 opposite strand (WDR83OS) encodes the 106-aa (amino acid) protein Asterix, which heterodimerizes with CCDC47 to form the PAT (protein associated with ER translocon) complex. This complex functions as a chaperone for large proteins containing transmembrane domains to ensure proper folding. Until recently, little was known about the role of WDR83OS or CCDC47 in human disease traits

Large biobank samples provide an opportunity to integrate broad phenotyping, familial records, and molecular genetics data to study complex traits and diseases. We introduce Pearson-Aitken Family Genetic Risk Scores (PA-FGRS), a method for estimating disease liability from patterns of diagnoses in extended, age-censored genealogical records. We then apply the method to study a paradigmatic complex

Balancing the tradeoff between quantity and quality of phenotypic data is critical in omics studies. Measurements below the limit of quantification (BLQ) are often tagged in quality control fields, but these flags are currently underutilized in human genetics studies. Extreme phenotype sampling is advantageous for mapping rare variant effects. We hypothesize that genetic drivers, along with environmental

Microtubule affinity-regulating kinase 2 (MARK2) contributes to establishing neuronal polarity and developing dendritic spines. Although large-scale sequencing studies have associated MARK2 variants with autism spectrum disorder (ASD), the clinical features and variant spectrum in affected individuals with MARK2 variants, early developmental phenotypes in mutant human neurons, and the pathogenic mechanism

Vitiligo is a common autoimmune disease characterized by patches of depigmented skin and overlying hair due to destruction of melanocytes in the involved regions. We investigated the relationship between vitiligo risk and vitiligo age of onset (AOO) using a vitiligo polygenic risk score that incorporated the most significant SNPs from genome-wide association studies. We find that vitiligo genetic risk

A recent publication describing the assembly of the Y chromosomes of 43 males was remarkable not only for its ambitious technical scope but also for the startling suggestion that the boundary of the pseudoautosomal region 1 (PAR1), where the human X and Y chromosomes engage in crossing-over during male meiosis, lies 500 kb distal to its previously reported location. Where is the boundary of the human

One of the regulatory mechanisms influencing the functional capacity of genes is alternative splicing (AS). Previous studies exploring the splicing landscape of human tissues have shown that AS has contributed to human biology, especially in disease progression and the immune response. Nonetheless, this phenomenon remains poorly characterized across human populations, and it is unclear how genetic

Gene-based burden tests are a popular and powerful approach for analysis of exome-wide association studies. These approaches combine sets of variants within a gene into a single burden score that is then tested for association. Typically, a range of burden scores are calculated and tested across a range of annotation classes and frequency bins. Correlation between these tests can complicate the multiple

Recent positive selection can result in an excess of long identity-by-descent (IBD) haplotype segments overlapping a locus. The statistical methods that we propose here address three major objectives in studying selective sweeps: scanning for regions of interest, identifying possible sweeping alleles, and estimating a selection coefficient s. First, we implement a selection scan to locate regions with

Research on brain expression quantitative trait loci (eQTLs) has illuminated the genetic underpinnings of schizophrenia (SCZ). Yet most of these studies have been centered on European populations, leading to a constrained understanding of population diversities and disease risks. To address this gap, we examined genotype and RNA-seq data from African Americans (AA, n = 158), Europeans (EUR, n = 408)

Pathogenic constitutional APC variants underlie familial adenomatous polyposis, the most common hereditary gastrointestinal polyposis syndrome. To improve variant classification and resolve the interpretative challenges of variants of uncertain significance (VUSs), APC-specific variant classification criteria were developed by the ClinGen-InSiGHT Hereditary Colorectal Cancer/Polyposis Variant Curation

As more patients receive genome-wide sequencing, the number of individuals diagnosed with multiple monogenic conditions is increasing. We sought to investigate the relative phenotypic contribution of dual diagnoses using both manual curation and computational approaches. First, we computed 1,003,236 semantic similarity scores for all possible pairs of 1,417 genes in the Developmental Disorder Gene2Phenotype

Whereas 16p11.2 BP4-5 copy-number variants (CNVs) represent one of the most pleiotropic etiologies of genomic syndromes in both clinical and population cohorts, the mechanisms leading to such pleiotropy remain understudied. Identifying 73 deletion and 89 duplication carrier individuals among unrelated White British UK Biobank participants, we performed a phenome-wide association study (PheWAS) between

Recurrent genomic rearrangements at 16p11.2 BP4-5 represent one of the most common causes of genomic disorders. Originally associated with increased risk for autism spectrum disorder, schizophrenia, and intellectual disability, as well as adiposity and head circumference, these CNVs have since been associated with a plethora of phenotypic alterations, albeit with high variability in expressivity and

Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH

The ClinGen Hereditary Breast, Ovarian, and Pancreatic Cancer (HBOP) Variant Curation Expert Panel (VCEP) is composed of internationally recognized experts in clinical genetics, molecular biology, and variant interpretation. This VCEP made specifications for the American College of Medical Genetics and Association for Molecular Pathology (ACMG/AMP) guidelines for the ataxia telangiectasia mutated (ATM)

The human reference genome (GRCh38), primarily sourced from individuals of European descent, falls short in capturing the vast genetic diversity across global populations. Efforts to diversify the reference genome face challenges in accessibility and representation, exacerbating the scarcity of African genomic data crucial for studying diseases prevalent in these populations. Sherman et al. proposed

Secondary findings (SFs) from genomic sequencing can have significant impacts on patient health, yet existing practices guiding their clinical investigation are inconsistent. We systematically reviewed existing SFs policies to identify variations and gaps in guidance. We cataloged and appraised international policies from academic databases (n = 5, inception-02/2022) and international human genetic

Hereditary hemorrhagic telangiectasia (HHT) is an inherited disorder of vascular malformations characterized by mucocutaneous telangiectases and arteriovenous malformations (AVMs) in internal organs. HHT is caused by inheritance of a loss of function mutation in one of three genes. Although individuals with HHT are haploinsufficient for one of these genes throughout their entire body, rather than exhibiting

Congenital microcoria (MCOR) is a rare hereditary developmental defect of the iris dilator muscle frequently associated with high axial myopia and high intraocular pressure (IOP) glaucoma. The condition is caused by submicroscopic rearrangements of chromosome 13q32.1. However, the mechanisms underlying the failure of iris development and the origin of associated features remain elusive. Here, we present

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015–2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines

The tumor immune microenvironment (TIME) plays key roles in tumor progression and response to immunotherapy. Previous studies have identified individual germline variants associated with differences in TIME. Here, we hypothesize that common variants associated with breast cancer risk or cancer-related traits, represented by polygenic risk scores (PRSs), may jointly influence immune features in TIME

Large-scale, multi-ethnic whole-genome sequencing (WGS) studies, such as the National Human Genome Research Institute Genome Sequencing Program’s Centers for Common Disease Genomics (CCDG), play an important role in increasing diversity for genetic research. Before performing association analyses, assessing Hardy-Weinberg equilibrium (HWE) is a crucial step in quality control procedures to remove low

We previously identified a homozygous Alu insertion variant (Alu_Ins) in the 3′-untranslated region (3′-UTR) of SPINK1 as the cause of severe infantile isolated exocrine pancreatic insufficiency. Although we established that Alu_Ins leads to the complete loss of SPINK1 mRNA expression, the precise mechanisms remained elusive. Here, we aimed to elucidate these mechanisms through a hypothesis-driven

To identify modifier loci underlying variation in body mass index (BMI) in persons with cystic fibrosis (pwCF), we performed a genome-wide association study (GWAS). Utilizing longitudinal height and weight data, along with demographic information and covariates from 4,393 pwCF, we calculated AvgBMIz representing the average of per-quarter BMI Z scores. The GWAS incorporated 9.8M single nucleotide polymorphisms

Same-sex sexual behavior has long interested genetics researchers in part because, while there is evidence of heritability, the trait as typically defined is associated with fewer offspring. Investigations of this phenomenon began in the 1990s with linkage studies and continue today with the advent of genome-wide association studies. As this body of research grows, so does critical scientific and ethical

Phenotype-driven gene prioritization is fundamental to diagnosing rare genetic disorders. While traditional approaches rely on curated knowledge graphs with phenotype-gene relations, recent advancements in large language models (LLMs) promise a streamlined text-to-gene solution. In this study, we evaluated five LLMs, including two generative pre-trained transformers (GPT) series and three Llama2 series

Gene therapy has made significant progress in the treatment of hereditary hearing loss. However, most research has focused on deafness-related genes that are primarily expressed in hair cells with less attention given to multisite-expressed deafness genes. MPZL2, the second leading cause of mild-to-moderate hereditary deafness, is widely expressed in different inner ear cells. We generated a mouse

A core task when establishing the strength of evidence for a gene’s role in a monogenic disorder is determining the appropriate disease entity to curate. Establishing this concept determines which evidence can be applied and quantified toward the final gene-disease validity, variant pathogenicity, or actionability classification. Genes with implications in more than one phenotype can necessitate a

Bicuspid aortic valve (BAV) is the most common congenital heart lesion with an estimated population prevalence of 1%. We hypothesize that specific gene variants predispose to early-onset complications of BAV (EBAV). We analyzed whole-exome sequences (WESs) to identify rare coding variants that contribute to BAV disease in 215 EBAV-affected families. Predicted damaging variants in candidate genes with

The BAF chromatin remodeler regulates lineage commitment including cranial neural crest cell (CNCC) specification. Variants in BAF subunits cause Coffin-Siris syndrome (CSS), a congenital disorder characterized by coarse craniofacial features and intellectual disability. Approximately 50% of individuals with CSS harbor variants in one of the mutually exclusive BAF subunits, ARID1A/ARID1B. While Arid1a

Variants that alter gene splicing are estimated to comprise up to a third of all disease-causing variants, yet they are hard to predict from DNA sequencing data alone. To overcome this, many groups are incorporating RNA-based analyses, which are resource intensive, particularly for diagnostic laboratories. There are thousands of functionally validated variants that induce mis-splicing; however, this

Retinitis pigmentosa (RP) is a Mendelian disease characterized by gradual loss of vision, due to the progressive degeneration of retinal cells. Genetically, it is highly heterogeneous, with pathogenic variants identified in more than 100 genes so far. Following a large-scale sequencing screening, we identified five individuals (four families) with recessive and non-syndromic RP, carrying as well bi-allelic

Multi-ancestry genome-wide association studies (GWASs) have highlighted the existence of variants with ancestry-specific effect sizes. Understanding where and why these ancestry-specific effects occur is fundamental to understanding the genetic basis of human diseases and complex traits. Here, we characterized genes differentially expressed across ancestries (ancDE genes) at the cell-type level by