HGG Advances最新文献

Polyglutamine (polyQ) disorders, such as Huntington disease (HD) and several spinocerebellar ataxias, are severe neurological disorders caused by glutamine codon repeat expansions. These conditions lack effective treatments, with therapeutic research focused on pathogenic gene knockdown. This investigation aimed to profile these genes using diverse human genomic data to inform therapeutic strategies by identifying new biology and assessing the potential on-target effects of knocking down these genes. We conducted an unbiased phenome-wide study to identify human traits and diseases linked to polyQ disorder genes (Open Targets L2G > 0.5). Network analyses explored shared trait associations and overlapping biological processes among these genes. Lastly, we assessed the theoretical druggability of polyQ disorder genes using recently identified features predictive of clinical trial success and compared them with repeat expansion (HD) modifier genes. Our analyses identified 215 human phenotype/polyQ disorder gene associations from 3,095 studies, indicating potential adverse effects from gene knockdown. Shared trait associations among genes suggested overlapping biological processes despite distinct functions. Drug target profile analysis revealed increased safety concerns due to genomic features (i.e., constraint, molecular interactions, and tissue specificity) for polyQ disorder genes, particularly ATN1, ATXN1, ATXN7, and HTT. PolyQ disorder genes also showed significantly more safety-related risks than HD genetic modifier genes (p = 7.03 × 10^-3). In conclusion, our analyses emphasize the pleiotropic nature of polyQ disorder genes, highlighting their potential risks as drug targets. These findings reinforce the importance of exploring alternative therapeutic strategies, such as targeting genetic modifier genes, as well as allele-selective approaches, to mitigate these challenges.

Bi-allelic loss-of-function (LoF) variants in SLC10A7 cause short stature, amelogenesis imperfecta, and skeletal dysplasia with scoliosis (SSASKS). Here, we report findings from an individual of Chinese ancestry with SSASKS carrying compound heterozygous splice-altering SLC10A7 variants: a previously reported pathogenic variant (NM_001029998.6:c.722-16A>G, paternal) and a de novo splice site variant (NM_001029998.6:c.472-1G>T, maternal). In silico predictions, minigene assays, and analyses of RNA and protein from the affected individual revealed that c.472-1G>T causes in-frame exon 7 skipping and c.722-16A>G induces out-of-frame exon 9 skipping. RNA sequencing of blood-derived cells showed that ∼32% residual SLC10A7 function in the affected individual, consistent with the 43% protein accumulation observed by western blot analysis of muscle tissue. These findings indicate that a previously presumed complete LoF allele instead results in partial LoF, prompting a refinement of the genotype-phenotype framework for SLC10A7-related SSASKS. This study highlights the challenges of predicting partial LoF effects, the value of RNA and protein analyses from affected individual-derived tissues, and the importance of distinguishing partial from complete LoF variants in the diagnosis and counseling of recessive disorders.

Stillbirth is a devastating adverse pregnancy outcome affecting 2 million pregnancies worldwide. Although an etiology may be found in some stillbirths, one-third remain unexplained. Stillbirth clusters in families and few underlying inherited genes associated with stillbirth are known. Well-characterized family-based studies may aid in identifying genetic contributors to unexplained stillbirth. Using the Utah Population Database, we defined pedigrees with high familial risk of stillbirth. Comprehensive phenotyping with review of primary medical records was conducted to identify stillbirth cases without identifiable causes. We generated whole-genome sequencing in seven stillborn placentas from three pedigrees. We performed shared genomic segments analysis to identify evidence for segregating haplotypes shared by the stillbirths to provide evidence for inherited risk. A region at 15q26.3 was identified in two independent pedigrees with genome-wide significance in both (a 1.2 Mb segment shared by two stillbirths in pedigree A, and a 1.8 Mb segment shared by two stillbirths in pedigree B). Four other regions reached genome-wide significance in single pedigrees at 16p13.13-p13.12, 9p13.3-p13.1, and 6p22.2-p22.1 (shared by the same two stillbirths in pedigree B), and a 0.8 Mb segment at 14q.32.2 shared by three stillbirths in pedigree C. The identified regions are implicated in in utero and postnatal development, pregnancy loss, and infertility. We identified evidence for inherited risk loci in stillbirth placental genes that are implicated in in utero and postnatal development, pregnancy loss, and infertility. Identification of inherited genes in stillbirth risk may provide therapeutic targets for prevention and treatment to improve pregnancy outcomes.

Rare diseases (RDs) collectively affect >400 million people worldwide, but fragmented infrastructure and biospecimen scarcity impede progress. China's heterogeneous healthcare landscape magnifies these challenges. Since 2016, Peking Union Medical College Hospital (PUMCH) RD Biobank has pioneered a scalable model integrating 446 institutions via national networks, and setup Quality Management System since 2019 with the ISO 20387:2018, that received accreditation in 2022. Our secure digital platform standardizes biospecimen protocols (acquisition/processing/storage) and enables ethical data/specimen sharing through auditable Material Transfer Agreements/Data Use Agreements. Among 49,759 enrolled patients, 73.13% were diagnosed, while 26.87% were undiagnosed, with pediatric cases (50.75%) and males (52.39%) predominating. Phenotypic analysis showed 78.51% single-system versus 21.20% multisystem involvement. Top diagnoses included congenital scoliosis and progressive muscular dystrophy. Specimen diversity revealed system-specific patterns: musculoskeletal/nervous/sensory systems linked to multiple specimen types; immune/genitourinary to fluids; cardiovascular/neoplastic to derivatives; endocrine uniquely to tissues. Nucleic acids (93.4%) and blood specimens (21.4%) formed core resources, while induced pluripotent stem cells/organoids prioritized for cardiovascular/neoplastic RDs enable functional validation. This framework transcends biospecimen fragmentation by uniting clinical, molecular, and institutional dimensions. It demonstrates how centralized governance and interoperable systems can accelerate RD research globally. By transforming isolated data into collaborative discovery engines, we provide a blueprint for converting RD challenges into precision diagnostics and therapies, which are urgently needed for the millions of individuals worldwide who remain undiagnosed.

Homozygous loss-of-function mutations in LNPK, the gene encoding the endoplasmic reticulum-associated protein lunapark, have previously been linked to an autosomal recessive neurodevelopmental syndrome. Here, we describe an individual harboring compound heterozygous predicted splice site mutations with an overall matching phenotype. In cultured fibroblasts, these mutations result in a dearth of transcript and severe loss of protein, thereby establishing their likely pathogenicity. The underlying reduction in gene expression is due to the activation of the nonsense-mediated decay (NMD) pathway as a consequence of exon skipping rather than intron retention, leading to aberrant transcripts. We further demonstrate that cells from the affected individual and her mother exhibit a significant increase in transcript compared with a control cell line when treated with an inhibitor of NMD, suggesting potential genetic compensation. Together, this report describes disease-causing variants in LNPK and reveals their impact on transcription and mRNA stability.

Microcephaly is a neurodevelopmental anomaly characterized by reduced head circumference and impaired brain growth, often accompanied by intellectual disability (ID), developmental delays, and seizures. While numerous genes have been implicated in microcephaly, the role of the SCF (Skp1-Cul1-F-box protein) ubiquitin ligase complex, particularly its core component CUL1, remains poorly understood. In this study, we identified heterozygous de novo and inherited variants in the CUL1 gene in four unrelated families with severe microcephaly, ID, and developmental delays. To investigate the functional consequences of CUL1 loss of function, we developed a zebrafish model with knockdown of cul1a&b, which exhibited significant reductions in central nervous system size and behavioral defects, mirroring the clinical phenotypes observed in patients. These findings establish CUL1 as a novel gene associated with severe neurodevelopmental disorders (NDDs) and highlight its critical role in brain development. Our study provides genotype-phenotype correlations for CUL1 in NDDs, expanding the genetic spectrum of disorders linked to the SCF complex and underscoring its importance in neurodevelopment.

Variants in SLC6A1 result in a rare neurodevelopmental disorder characterized by a variable clinical presentation of symptoms including developmental delay, epilepsy, motor dysfunction, and autism spectrum disorder. SLC6A1 haploinsufficiency has been confirmed as the predominant pathway of SLC6A1-related neurodevelopmental disorder (SLC6A1-NDD); however, the molecular mechanism underlying the variable clinical presentation remains unclear. Here, through work of the Undiagnosed Diseases Network, we identify an individual with an inherited p.A334S variant of uncertain significance. To resolve this variant and better understand the variable expressivity associated with SLC6A1, we assess the phenotypes of the proband in comparison with a cohort of 13 individuals diagnosed with SLC6A1-NDD. We then create an allelic series in Drosophila melanogaster to functionally characterize these variants. Informatic clustering based on these clinical findings points to significant clinical overlap between the unsolved individual and confirmed SLC6A1-NDD. We confirm phenotypes in flies expressing SLC6A1 variants consistent with a partial loss-of-function mechanism. We conclude that the p.A334S variant is a hypomorphic allele and begin to elucidate the underlying variability in SLC6A1-NDD. These insights will inform clinical diagnosis, prognosis, intervention, and inform therapeutic design for those living with SLC6A1-NDD.

Heart failure (HF) is a common cardiovascular syndrome that poses significant morbidity and mortality risks. While genome-wide association studies reporting on HF abound, its genetic etiology remains poorly elucidated, primarily due to its inherent polygenic nature. Furthermore, these genetic insights have not been fully leveraged to develop effective primary treatment strategies for HF. In this study, we conducted a large-scale integrated multi-trait analysis using European ancestry genome-wide association study summary statistics of coronary artery disease and HF, involving nearly 2 million samples to identify risk loci associated with HF. Seventy-two loci were identified for HF using MTAG, of which 58 were supported in the replication phase. Transcriptome association analysis revealed 215 HF risk genes, including EDNRA and FURIN. Pathway enrichment analysis of risk genes revealed their enrichment in pathways closely related to HF, such as response to endogenous stimulus (adjusted p = 8.83 × 10^-3), phosphate-containing compound metabolic process (adjusted p = 1.91 × 10^-2), myofibroblast differentiation (adjusted p = 4.26 × 10^-2), and regulation of muscle adaptation (adjusted p = 4.96 × 10^-2). Single-cell analysis indicated significant enrichments of these genes in smooth muscle cells, fibroblasts of cardiac tissue, and cardiac endothelial cells. Additionally, our analysis of HF risk genes identified 81 potential drugs for further pharmacological evaluation. These findings provide insights into the genetic determinants of HF, highlighting MTAG-identified genetic loci as potential interventional targets for HF treatment, with significant implications for public health and clinical practice.

To advance understanding of cellular heterogeneity in disease from single-cell sequencing data, we introduce residual principal-component analysis (ResidPCA), a robust method for identifying cell states that explicitly models cell-type heterogeneity. In simulations, ResidPCA achieved more than 4-fold higher accuracy than conventional PCA and over 3-fold higher accuracy than non-negative matrix factorization (NMF)-based methods in detecting states expressed across multiple cell types. Applied to single-cell RNA sequencing of light-stimulated mouse visual cortex cells, ResidPCA captured stimulus-driven variability with an accuracy more than 5-fold higher than NMF-based approaches. In single-nucleus datasets from an Alzheimer disease cohort, ResidPCA identified 44 chromatin accessibility-based states from single-nucleus ATAC-seq (snATAC-seq) and 42 transcriptional states from single-nucleus RNA-seq. Thirty snATAC-seq states were significantly enriched for Alzheimer disease heritability, often more so than established cell types such as microglia. The snATAC-seq state most significantly enriched for heritability further elucidates a recently implicated neuron-oligodendrocyte-microglial mechanistic axis, linking early amyloid production in neurons and oligodendrocytes with later microglial activation and immune response. These results highlight the ability of ResidPCA to uncover previously hidden biological variation in single-cell data and reveal disease-relevant cell states.

Telomere biology disorders (TBDs) are caused by rare pathogenic variants in telomere maintenance genes and often present with variable penetrance of multi-organ system manifestations. We evaluated a family with 14 individuals heterozygous for TERT c.2591T>C (p.L864P) and 13 non-carriers. TRAP assays showed that p.L864P causes a complete loss of telomerase activity. Carriers had shorter lymphocyte telomeres than non-carriers. Carriers presented different TBD manifestations, but had similar telomere length (TL) distributions, suggesting variable penetrance and possible genetic anticipation. Somatic TERT promoter mutations were detected in four carriers aged >50 years (variant allele fractions <4% in three and 18%-19% in one). Exome sequencing did not identify other variants of interest. Although not statistically significant, polygenic scores derived from common TL-associated genetic variation were lower in c.2591T>C carriers with more TBD clinical manifestations. Alleles associated with alternative TERT splicing, VNTR6-1-Long and rs10069690-T, co-segregated with c.2591T>C. This haplotype was associated with a reduction in TL Z score (β = -1.81, p < 0.0001). Another haplotype, c.2591T, VNTR6-1-Long, and rs10069690-T, demonstrated an independent reduction of TL Z score (β = -0.84, p = 0.0111). The TBD manifestations in this family may relate to common TL-associated genetic variation and alternative TERT splicing, emphasizing the importance of investigations into TBD manifestations within and between TBD families.