Human molecular genetics最新文献

Background: American Indians and Hispanics/Latinos have a high burden of chronic kidney disease (CKD) and they may share disease associated genetic variants. This study aims to identify loci for CKD and albuminuria that are shared between these populations.

Methods: We performed genome-wide association studies (GWAS) in 3157 American Indians and 12 625 Hispanics/Latinos for CKD (estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2) and albuminuria (urine albumin to creatinine ratio [uACR]) > 30 mg/g). We examined significant associations across GWASs and the functional relevance of findings.

Results: Five low-frequency variants at chromosome 7 were significantly associated with albuminuria in American Indians (lead variant: rs4370473, intronic to KCND2, P = 8.93 × 10-9), with evidence for a partly independent association driven by rs7791185 (p conditional on rs4370473 = 3.8 × 10-5). A chromosome 11 variant (rs59232451, HBE1-HBB locus, P = 4.9 × 10-8) was significantly associated with albuminuria in Hispanics/Latinos when adjusting for diabetes, and the association was partially accounted for by the HBB rs344. The associations for albuminuria did not cross-replicate among studies. There were no significant associations with CKD.

Conclusions: Our study identified associations at KCND2 in American Indians and HBE1-HBB in Hispanics/Latinos for albuminuria. Findings suggest differences in genetic architecture influencing albuminuria across these populations.

A vascular anomaly could be a vascular tumor or a vascular malformation. Vascular malformation is subclassified into fast-flow, including arteriovenous malformation and portwine stain, and slow-flow group comprising venous malformation, lymphatic malformation, and venolymphatic malformation. Recent data have shown that somatic mutations of genes in PIK3/AKT/mTOR and RAS/MAPK/ERK pathways are a major cause of this disorder. We conducted a gene panel testing (129 genes) with high-depth next-generation sequencing (NGS), which can detect very low-level mosaicism (~ 1%), on the tissue obtained from 26 patients in a cohort of mixed types of vascular malformation, comprising 2 fast-flow and 24 slow-flow malformations. Pathogenic/likely pathogenic (P/LP) variants were identified in 21 of 26 patients, yielding the overall diagnostic rate of 80.8%. The leading causes identified were PIK3CA (57.1%) and TEK (33.3%), especially in the slow-flow group, whereas HRAS and GNAQ were found positive in patients with fast-flow malformations. Three of 11 P/LP variants were previously unreported in vascular malformation, including those from HRAS, PIK3CA, and TEK. Most variants were detected as a solo, except for double mutations of TEK in patients with blue rubber bleb nevus syndrome (BRBNS) and a non-syndromic venous malformation. The level of mosaicism in the tissue ranged from 0.93% to 16.53%, with 60% (15/25) of the variants having ≥ 5% mosaicism. Three variant of uncertain significance of IDH1 and NACC1 were found and deserve further investigation for their pathogenic role. Data from the present study suggest the potential benefit of targeted therapy, in particular drugs in the mTOR pathway, for these patients.

Spinal Muscular Atrophy (SMA) is characterized by a reduction of survival of motoneuron (SMN) protein, resulting in proximal muscle atrophy. SMA is a multi-system disease involving patients with alterations in multiple organs and metabolic pathways. Approved therapies focus on increasing SMN protein level either in the central nervous system or systemically. However, none of these therapies result in a cure. Patients show perturbations in several organs, including altered lipid metabolism such as leptin proteohormone levels, dicarboxylic aciduria and altered β-oxidation. In this study, we describe alterations along the neuroendocrine axis of leptin homeostasis in white adipose tissue (WAT) and hypothalamus of the severe Taiwanese SMA mouse model. Body weight was significantly decreased in SMA mice accompanied by significantly changed leptin protein levels in WAT of pre-symptomatic (P3) mice. Additionally, transcriptome and proteome analyses of WAT and hypothalamus revealed alterations in lipid and glucose metabolic pathways. We also identified several altered targets associated with appetite regulation. Our findings emphasize dysregulations in lipid and glucose metabolism and reinforce the need for research on metabolism in a disease with a predominant neuromuscular phenotype.

SUPT16H encodes a subunit of the FACT (FAcilitates Chromatin Transcription) complex, a histone chaperone essential for maintaining chromatin integrity during transcription, replication, and DNA repair. Pathogenic de novo SUPT16H missense variants have previously been linked to neurodevelopmental disorders in eight individuals. Here, we expand the genotypic and phenotypic spectrum by identifying 24 additional individuals harboring ultrarare heterozygous missense or truncating variants, who share overlapping clinical features including intellectual disability, autism spectrum disorder, hypotonia, and characteristic craniofacial dysmorphism. To elucidate the underlying mechanisms, we generated a supt16h knockout zebrafish model using CRISPR/Cas9. The supt16h loss-of-function (LOF) model recapitulated key patient phenotypes such as developmental delay, craniofacial anomalies, and hypotonia. Structural and functional analyses of selected SUPT16H variants demonstrated differential rescue of developmental defects in supt16h-deficient embryos, indicating variant-specific LOF effects in vivo. The presence of non-neural manifestations, including facial and ear anomalies, suggested a role for SUPT16H in neural crest development. Consistently, supt16h loss impaired neural crest cell migration and differentiation and triggered p53-dependent apoptosis in the central nervous system (CNS) and neural crest-derived pharyngeal arches. Notably, supt16h deficiency impaired oligodendrocyte specification in the CNS and perturbed differentiation of neural crest-derived Schwann cells in the peripheral nervous system, providing a plausible basis for hypotonia. These findings uncover a previously unrecognized role of SUPT16H in neural crest development, linking chromatin regulation to neural crest-derived lineage specification and differentiation, thereby defining SUPT16H deficiency as a neurocristopathy that broadens the clinical and mechanistic landscape of SUPT16H-associated disorders.

Despite advances in exome and genome sequencing, many patients with suspected genetic disorders remain undiagnosed due to limitations in detecting complex structural variants. This study aimed to evaluate the diagnostic yield and clinical utility of Full-Genome Analysis (FGA), an integrated approach that combines short-read whole-genome sequencing (WGS), 10x Genomics linked-read sequencing, and Bionano optical genome mapping (OGM). Twenty-nine patients with unclear or inconclusive genetic diagnoses after standard testing were analyzed using an in-house FGA pipeline capable of simultaneously detecting single nucleotide variants (SNVs), copy number variants (CNVs), and structural variants (SVs). FGA established molecular diagnoses in 12 of 29 patients (41.4%), identifying nine pathogenic SNVs, three CNVs, and two complex SVs. Two CNVs were missed by chromosomal microarray, and both SVs were undetectable by short-read WES or WGS. Representative cases demonstrated that integrating OGM and linked-read sequencing improved detection of compound heterozygous variants and cryptic rearrangements that conventional methods failed to resolve. FGA substantially improved the diagnostic yield in patients with unresolved genetic disorders after conventional testing. Its ability to comprehensively detect small and large genomic variants within a single workflow highlights its potential as a next-generation diagnostic platform for rare disease evaluation.

Cardiotoxicity is a therapeutic challenge for anthracycline-based treatments for solid tumors and leukemia. Genome-wide association studies have revealed that single nucleotide polymorphisms in the SLC28A3 locus (encoding Concentrative Nucleoside Transporter 3, CNT3) are significantly associated with reduced doxorubicin-induced cardiotoxicity. However, the mechanistic understanding of the functional effects of these genomic variants is lacking. We designed studies focused on clinically associated SNPs within SLC28A3 using minigenes, site-directed mutagenesis, splicing assays, modulation of SLC28A3 and its antisense long noncoding RNA (lncRNA, AS1), and doxorubicin transport and cytotoxicity measurements to gain more insight. We demonstrated that the cardioprotective synonymous SNP rs7853758 in the Ex14 coding region of SLC28A3 and the variant rs11140490 in Ex1 of its antisense lncRNA (SLC28A3-AS1) have functional consequences in regulating CNT3 transcript and protein expression using alterations in RNA levels and alternative splicing. Additionally, the deep intronic region of Int13, which harbors the SNP rs7030019, is critical for the splicing of CNT3 precursor mRNA at Ex13-14. Furthermore, we identified alternatively spliced variants of the AS1 lncRNA that differentially regulate CNT3 gene expression, doxorubicin transport, and cytotoxicity. Together, these findings suggest that antisense and splicing mechanisms may be exploited to modulate CNT3 function to reduce doxorubicin cytotoxicity, enabling the development of predictive biomarkers and chemotherapeutic management of anthracycline toxicities.