HGG Advances最新文献

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer, with Hispanic/Latino children having a higher incidence of ALL than other racial/ethnic groups. Among the genetic variants previously implicated in ALL risk, a number of them were found to be enriched in Indigenous American (IA)-like ancestries and inherited by many Hispanic/Latino individuals. However, due to potential confounding from environmental factors, the association between IA-like ancestry and risk for ALL has remained unclear. In this study, we characterized the impact of IA-like ancestry on overall ALL risk and on the frequency and effect size of known risk alleles, while accounting for non-genetic correlates of ancestry. Contrary to previous findings, we found that global IA-like ancestry was not significantly associated with ALL risk after adjusting for socioeconomic indicators. However, locally at known ALL risk regions, we uncovered that increasing copies of the IA-like haplotype were positively and significantly associated with ALL risk (e.g., the IA-like haplotype had ∼1.33 times the odds of harboring the risk allele compared to non-IA-like haplotypes), but we found no evidence of interaction between genotype and ancestry in relation to ALL. Admixture mapping identified replicable association signals at chr7p12.2 and chr10q21.2, consistent with the benefit of leveraging genetic ancestry in identifying genetic risk loci. Our results suggest that increased risk of ALL in Hispanic/Latino children may be conferred by the higher frequency of risk alleles within IA-like ancestry and that local ancestry-based analyses are robust strategies to elucidate genetic etiology of disease.

Human development is a complex process that requires precise control of gene expression through regulatory proteins. Recently, heterozygous variants in PRR12, encoding a proline-rich regulatory protein, were found to cause a variable phenotype involving developmental delay/cognitive impairment, neuropsychiatric diagnoses, structural eye anomalies, congenital heart and kidney defects, and poor growth. QSER1, encoding glutamine- and serine-rich protein 1, represents a paralog of PRR12 that shares 28% overall identity at the protein level and stronger conservation (43%) in the C-terminal region. QSER1 deficiency in human embryonic stem cells causes hypermethylation of many key transcription factor genes, implicating it in the development of multiple organs. Here, we present three unrelated individuals with neurodevelopmental phenotypes, variable other multisystem anomalies, and heterozygous variants in QSER1. This includes two novel de novo frameshift alleles (p.(Lys1565Argfs∗36) and p.(Phe896fs∗28)) and one ultra-rare canonical splice site variant resulting in a combination of abnormal transcripts, frameshift (p.(Glu1393Glyfs∗26)), and in-frame deletion of a conserved amino acid (p.(Glu1393del)), supported by in silico predictions and minigene assays. In situ hybridization revealed dynamic and broad expression of qser1 in zebrafish embryos, including a strong presence in the developing brain. These data suggest a possible role for QSER1/qser1 in vertebrate development and human disease.

SATB2-associated syndrome is an autosomal dominant neurodevelopmental syndrome caused by genetic alterations in the transcription factor SATB2. The associated phenotype is variable, and genotype-phenotype correlation studies have not yet been able to explain differences in severity and symptoms across affected individuals. While haploinsufficiency is the most often described disease mechanism, with the majority of variants consisting of whole- or partial-gene deletions and protein truncating variants with predicted loss of function, approximately one-third of affected individuals carry a SATB2 missense variant with an unknown effect. In this study, we sought to functionally characterize these missense variants to uncover associated pathogenic mechanisms. We combined a set of human cell-based experiments to screen 31 etiological SATB2 missense variants for effects on nuclear localization, global chromatin binding, and transcriptional activity. Our data indicate partial loss-of-function effects for most of the studied missense variants but identify at least eight variants with increased SATB2 function showing a combination (or subset) of features that include stronger co-localization with DNA, decreased nuclear protein mobility suggesting increased overall chromatin binding, and maintained or increased transcriptional activity. These results demonstrate that phenotypes associated with variants in SATB2 may have distinct underlying disease mechanisms, and the data could provide a resource for future studies investigating disease variability and potential therapies for this condition.

Morphine is a potent analgesic and exhibits significant efficacy in alleviating severe pain. However, prolonged use can lead to drug dependency. Moreover, there are individual variations in response to and tolerance of morphine, indicating potential genetic regulation. Nevertheless, the mechanisms underlying these phenomena remain unclear. Therefore, we aimed to systematically dissect the genetic regulatory network for morphine response. We used quantitative trait locus mapping to identify genetic regions associated with morphine-related traits. Candidate genes for each locus were further filtered based on multiple criteria, including gene-trait association, cis-regulation, genetic variation, and potential function. The results showed that morphine response-related behavioral traits were significantly influenced by genetic background. Using the GEMMA and HK algorithms, we identified 18 genomic loci associated with dozens of morphine response-related traits. This includes loci previously studied on chromosome 10, together with a locus on chromosome 5 (0-20 Mb) identified in our analysis which showed the most association outside chromosome 10. Additionally, we identified six candidate functional genes (Cacna2d1, Myo7a, Elovl4, Oprm1, Cdk12, and Ccdc88c) that passed the filtering criteria. Oprm1 encodes the μ-opioid receptor, while Cacna2d1, Cdk12, and Elovl4 are closely associated with neurons. Myo7a and Ccdc88c may mediate anxiety and cognitive dysfunction caused by morphine dependence. Furthermore, Oprm1, Cacna2d1, and Ccdc88c are associated with opioid use disorders, nerve measurements, and brain volume in humans. In summary, our study describes the genetic regulation landscape of morphine response in BXD mice and identifies six candidate genes, providing valuable opportunities for further exploration.

5-Methylcytosine (5mC) is the most common DNA modification in the human genome. Bisulfite conversion combined with short-read sequencing captures this modification at single-nucleotide resolution but introduces PCR duplication bias and limits co-methylation analysis between distant cytosines. To resolve these limitations, we used nanopore long-read sequencing to profile human methylation and performed long-range co-methylation analysis with native DNA modification information. We analyzed the nanopore demo data in the adaptive sampling sequencing targeting the CpG islands and applied the linkage disequilibrium (LD) R² to identified methylation haplotype blocks (MHBs). We found that the cancer genome exhibited significantly smaller MHBs, higher CpG density, and a lower methylation LD R² value compared to normal cells. Additionally, we demonstrated the superiority of long-read sequencing in capturing large MHBs compared with short-read sequencing. By profiling the methylation changes near the JASPAR motif and actual chromatin immunoprecipitation sequencing (ChIP-seq) peaks, we also studied the epigenetic changes related to protein binding. Based on adaptive sampling technology, we conducted nanopore sequencing targeting regions with methylation quantitative trait loci (mQTLs) and genome-wide association study (GWAS) risk variants in the 22Rv1 cell line. After analyses, we inspected the closest haplotype-specific methylated region near the variant and identified allele-specific methylated regions with allele-specific accessibility signals in the ATAC-seq data. This study demonstrates the feasibility of nanopore sequencing for methylome profiling while preserving haplotype information, offering an innovative approach to elucidate the epigenetic changes driven by noncoding variants in the human genome.

Telomere length (TL) is a key indicator of biological aging. Understanding the association between TL and cognitive impairment may provide important insights into disease mechanisms for age-related neurodegenerative disorders, such as Alzheimer's disease (AD). However, the relationship between TL and cognitive function remains controversial, with studies reporting positive, negative, or no associations between them. This inconsistency may be attributed to genetic and environmental variations or differences in TL measurement methods. We conducted a comprehensive characterization of DNA sequence-determined TL and analyzed its association with cognitive function in the Midwestern Amish. The Midwestern Amish are a founder population demonstrating reduced genetic and environmental variation compared with the general European population. This unique population structure allowed us to better control for potential confounding by non-telomere genetic and environmental factors. Our study confirmed the expected telomere shortening with age and provided both SNP-based and pedigree-based TL heritability estimates. No significant correlation was observed between TL and cognitive function. However, a genome-wide association study of TL revealed three loci associated with TL, each containing Amish-enriched rare variants.

Asymptomatic individuals with pathogenic variants in OTC, the gene encoding ornithine transcarbamylase are increasingly being identified through cascade testing, carrier screening, or as secondary findings from genome-wide sequencing tests. However, guidance for counseling and management of such individuals is currently lacking. We selected two common OTC variants for phenotypic and functional characterization: NM_000531.6:c.118C>T p.(Arg40Cys) and NM_000531.6:c.1061T>G p.(Phe354Cys). The former is the most frequently reported pathogenic/likely pathogenic missense variant present in gnomAD, and the latter has been frequently encountered in our clinical practice. We performed a retrospective chart review at our center, queried the database of the Urea Cycle Disorders Consortium, and performed a literature review to create cohorts of individuals with these variants. Functional studies were pursued using a validated yeast-based assay. We identified 14 individuals (6 females, 8 males) with the p.(Arg40Cys) variant and 14 individuals (5 females, 9 males) with the p.(Phe354Cys) variant. There were no reported episodes of neonatal hyperammonemia in males and no hyperammonemic events reported in females with either variant. In our functional assay, both variants reduced yeast growth to the hypomorphic range. Our findings support the classification of both p.(Arg40Cys) and p.(Phe354Cys) variants in OTC as hypomorphic variants that are typically associated with late-onset OTCD in males.

Accurate inference of genetic ancestry is a fundamental step in population genetics, disease association studies, and understanding human history. However, most existing tools, whether model-based or model-free, are limited by dataset-specific characteristics, which restrict reproducibility and hinder cross-study comparisons. Additionally, these tools often struggle to resolve fine-scale population structure, requiring multiple processing steps, such as sample subsetting and repeated program execution. These practices introduce bias and reduce replicability, particularly in evolutionary and migration studies. We present GrafAnc, a robust tool for inferring ancestry at both continental and subcontinental levels without requiring dataset partitioning, iterative processing, or manual sample curation. Building upon and extending GRAF-pop, GrafAnc infers an individual's ancestry background by comparing genotypes with allele frequencies from 26 reference populations compiled from publicly available databases. The current version of GrafAnc generates 18 ancestry scores per individual and classifies individuals into 8 continental and 38 subcontinental ancestry groups, including Middle East and North Africa. These scores are invariant to the specific composition of the study dataset and can be used directly as continuous covariates or for ancestry group assignments. GrafAnc enables seamless integration of population structure across studies and datasets, facilitating consistent interpretation in large-scale genomics. We benchmark GrafAnc using the 1000 Genomes Project, UK Biobank, and Human Genome Diversity Project datasets, demonstrating its accuracy and robustness across diverse ancestries and genotyping platforms. GrafAnc is implemented in C++ with multithreading support and is freely available.

Loose anagen hair syndrome is a form of childhood-onset non-scarring alopecia marked by easily and painlessly plucking terminal hair during its active growth, or anagen, phase. It is believed to result from poor hair shaft anchoring within the follicle due to premature keratinization. Our study identified a plausibly pathogenic variant in KRT32 (c.296C>T; p.Thr99Ile) that co-segregates with the phenotype in a large family. This study aimed to explore the role of KRT32, previously unassociated with loose anagen hair, in hair anchorage and assess the functional impact of its p.Thr99Ile variant. We hypothesized that the p.Thr99Ile variant reduces the binding affinity of KRT32 to KRT82, disrupting the intermediate filament structure in the hair shaft cuticle and leading to weak anagen hair anchorage. To test this hypothesis, we conducted a protein-protein interaction assay using far-western blotting and performed in silico intermediate filament network segmentation analysis on high-resolution fluorescent microscopy images. Our results showed a decreased binding affinity of KRT32^Thr99Ile to KRT82 when compared to KRT32^WT. There were significant differences in segment count and filament thickness, as measured by brightness, between the KRT32^Thr99Ile and the KRT32^WT. We conclude that the c.296C>T variant of KRT32 is associated with loose anagen hair phenotype.

Lamins A/C, coded by LMNA gene, are crucial for nuclear architecture preservation. Pathogenic LMNA variants cause a wide range of inherited diseases called "laminopathies". A subgroup is referred to "progeroid syndromes" characterized by premature aging and other manifestations including cardiac valve abnormalities. Atypical phenotypes, generally less severe, have also been reported. We report the case of a 26-year-old male with calcific tricuspid aortic and mitral valve diseases. His father was diagnosed with severe aortic valve stenosis and mitral annulus calcification at the age of 38. The goal of this study was to identify the putative variant causing this non-syndromic multivalvular disease. Known disease-causing variants in NOTCH1, FLNA, and DCHS1 were first excluded by Sanger sequencing. Whole-exome sequencing was then performed in five family members. A LMNA variant (p.Glu262Val) was identified with in silico evidences of pathogenicity (CADD [combined annotation dependent depletion] = 33). Cells transfected with the cDNA construct harboring p.Glu262Val were characterized by abnormal nuclear morphology. Along with a literature review, the variant was classified as likely pathogenic. Elucidating the mechanism by which LMNA p.Glu262Val specifically affects cardiac heart valves is likely to provide insight about the pathogenesis of Mendelian forms of valvular heart diseases and may help guide the development of therapies.