Annals of Human Genetics最新文献

Introduction: Dyslipidemia is a heterogeneous group of disorders that typically presents asymptomatically during childhood but increases the risk of atherosclerotic cardiovascular disease later in life. Understanding the genetic basis can provide valuable insights for early diagnosis and may support more tailored therapeutic approaches. This study aimed to investigate the genetic etiology of childhood-onset dyslipidemia and explore genotype-phenotype correlations.

Methods: We retrospectively analyzed genetic data from 133 pediatric patients evaluated for suspected dyslipidemia between 2018 and 2023. Targeted next-generation sequencing (NGS) was performed using a panel covering 20 genes associated with lipid metabolism. Only pathogenic or likely pathogenic variants were included in the analysis.

Results: Pathogenic or likely pathogenic variants were identified in 17% of patients (n = 23). The most frequently affected gene was LDLR (74%), followed by significant variants in APOB, APOA5, LDLRAP1, and ALMS1. Three novel pathogenic variants were identified in this cohort: a splice-site variant in LDLRAP1 (c.231+2T>C) and two truncating variants in APOB (p.Tyr992Ter and p.Lys576Ter). Genotype-phenotype analysis revealed distinct impacts of variant types on lipid profiles. Notably, APOB variants were associated with both hypercholesterolemia and hypocholesterolemia.

Conclusion: Our findings highlight the substantial contribution of genetic factors to childhood dyslipidemia and underscore the clinical utility of genetic testing in guiding diagnostic and therapeutic decisions.

Background: Clubfoot, or talipes equinovarus (TEV), is an autosomal dominant foot malformation characterized by a variable clinical picture, ranging from mild to severe deformity. While its genetic basis has been partly elucidated, the underlying molecular mechanisms remain incompletely understood.

Methods: We investigated a five-generation Polish family presenting autosomal dominant clubfoot associated with arthrogrypotic hand deformation. Genotyping was performed to identify variants co-segregating with the phenotype. Aberrant splicing effects were assessed in the proband's sample, and functional validation was carried out in zebrafish.

Results: Two variants were identified that segregated with the phenotype. The first, TMEM256 c.118-4dup, is an intronic duplication resulting in aberrant splicing. The pathogenicity of the misspliced TMEM256 products was confirmed in zebrafish. The second variant, MYH3 c.1123G>A;p.(Glu375Lys), is a previously reported missense change potentially explaining the arthrogryposis-like hand deformations in the affected family members.

Conclusions: Our findings reveal TMEM256 as a potential novel candidate gene for clubfoot and highlight the contribution of MYH3 variants to the broader clinical spectrum observed. These findings contribute to understanding the genetic complexity underlying clubfoot, providing unique insights into potential novel candidate gene and pathways involved in this condition.

Background: With the increasing prevalence of neurological disorders, such as Alzheimer's disease (AD), Parkinson's disease (PD), and epilepsy (EP) worldwide, there is a growing burden on medical and healthcare resources. Therefore, it is crucial to identify the etiology of these diseases and implement targeted preventive, diagnostic, and treatment measures to address the existing shortage of medical resources. Lipids are integral components of biological membranes. They not only function in energy storage and maintaining cell structure but also play a pivotal role in intercellular communication and signal transmission. Hence, lipids may hold significant implications in the pathogenesis and progression of the aforementioned disorders.

Methods: Utilizing two-sample Mendelian randomization (MR) in this investigation, the IEU OpenGWAS database was analyzed to explore the potential causal association between 159 lipids and the mentioned conditions, with sensitivity analysis being performed. Differentially expressed genes (DEGs) were obtained through data analysis of these three diseases in the GEO database, followed by enrichment analysis and protein-protein interaction (PPI) network analysis.

Results: The findings indicated a potential causal association between the onset and progression of these disorders and 20 lipids categorized into six groups, which include sterol esters (SEs), ceramides (Cer), phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and triacylglycerol (TAG). Furthermore, these lipids were found to regulate biological processes and pathways associated with endocytosis, synaptic vesicular circulation, signal release, MAPK signaling pathway, PI3 kinase (PI3K)-AKT signaling pathway, dopaminergic synapses, and malaria infection. It is worth noting that based on the comprehensive scores of protein interactions in the STRING database, as well as their connectivity and association strength with other proteins in the network, heat shock factor binding protein 1 (HSPB1), which is closely related to lipids and has a relatively close relationship with diseases, was identified as a key protein for AD. Similarly, RAB3A was identified as a key protein for PD. CD160 serves as the key protein of EP.

Conclusion: This study, by combining MR with bioinformatics analysis, discovered the potential lipid-based biological processes, pathways, and biomarkers of AD, PD, and EP, respectively, suggesting new therapeutic targets for us, deepening our understanding of the mechanisms of neurological diseases, and providing support for future clinical interventions.

Objective: To explore the clinical presentation and genetic etiology of a child with intellectual disability, speech developmental delay, learning difficulties, behavioral stereotype, and obsessive-compulsive disorder, and to identify new variants.

Methods and results: In this study, Karyotype and copy number variant sequencing (CNV-seq) were performed to detect chromosome abnormalities in this family. The whole exome sequencing (WES) was performed to investigate additional genetic variants in this family. Minigene array was used to verify whether the novel variant c.1027-2A>G really affected the splicing of STAG1 gene. Chromosomal karyotyping and CNV-seq analysis did not reveal any chromosomal abnormalities. The WES result demonstrated a de novo NM_005862.3:c.1027-2A>G variant in STAG1 gene in the patient. This splicing variant was classified as likely pathogenic based on ACMG/AMP guidelines. Minigene array results showed that the variant could result in the appearance of premature termination codon.

Conclusion: Our study identified a novel pathogenic locus, c.1027-2A>G, associated with Intellectual developmental disorder, autosomal dominant 47 (MRD47).

This review addresses the genetics of acne vulgaris, the most common skin disease. It is characterized by the presence of comedones (blackheads), papules, and pustules. The condition is associated with sebaceous glands in the face and chest, which produce an oily substance called sebum. In developed nations, acne affects over 80% of adolescents. Mild disease usually resolves spontaneously. More severe acne can leave permanent, disfiguring scarring and strongly affects quality of life. In those cases, medical intervention is warranted. To date, antibiotics and retinoids (synthetic vitamin A derivatives) are the mainstays of treatment. Depending on the severity of the condition, these drugs may be administered either topically or systemically.

Whilst generally effective, they do come with significant drawbacks. Antibiotic use for treating acne is contributing to antimicrobial resistance. In addition, indiscriminate eradication of the skin microbiome negatively impacts skin health. Retinoids are teratogenic and have other undesirable side effects, such as skin irritation and increased UV sensitivity. Thus, there is a clear need for effective interventions that target the underlying disease mechanism, minimizing side effects.

Rapid progress has recently been made in understanding the mechanisms underlying acne. For decades, it was assumed that blackhead formation results from the accumulation of sebum in the hair follicle opening, due to increased sebum production at the onset of puberty. Subsequent colonization by the commensal bacterium Cutibacterium acnes then was thought to cause inflammation. It was also postulated that this micro-organism could induce blackheads. There are, however, several problems with this supposed sequence of events, not the least of which is that it doesn't explain how retinoids work, or why sebaceous glands associated with blackheads are atrophic and hence produce less sebum, not more.

Both GWAS and single gene disorders unequivocally indicate stem/progenitor cell maintenance and cellular migration as the most important processes in the pathogenesis of acne. Together with insights from mouse models, this new perspective is transforming the way we think about acne and its treatment.

Germline pathogenic variants (GPVs, ‘mutations’) causing inherited susceptibility to certain cancers (cancer susceptibility genes, CSGs) broadly belong to one of two main classes—loss of function variants in tumour suppressor genes (TSGs) or gain of function variants in proto-oncogenes (an over-simplification). Genomic analyses of tumours identify ‘driver mutations’ promoting tumour growth and somatic variants which contribute to ‘mutation signatures’ which, with histopathology, can be used to subclassify cancers with implications for causality and treatment. The identification of susceptible individuals is important, as they and their relatives may be at elevated risk of tumours, and this can influence optimal cancer treatment. Classically, cancer risk assessment utilises family history, lifestyle/environment factors, and any non-neoplastic clinical findings, followed by genetic testing of high/moderate penetrance CSGs. In cancer cases not caused by highly penetrant CSGs, multiple variants conferring relatively small risks play a major role. These were discovered by genome-wide association (GWAS) studies. The utility of polygenic risk scores (PRS) derived from multiple such variants for clinical risk profiling is being assessed. Access to genetic tests is improved by widening eligibility criteria for testing and empowering non-genetic clinicians to identify CSG GPVs and manage carriers. This will contribute to expanding programmes of screening, prevention and early detection (SPED), with personalised surveillance and prophylactic interventions, and exploit knowledge of the molecular mechanisms of cancer susceptibility to develop novel cancer therapies. In some jurisdictions, population testing is being considered, but GPV penetrance in this setting can be unclear, and the public health implications are complex.