Annals of Human Genetics最新文献

Objective: This study aimed to determine the prevalence of Duffy, HbS, HbC, G6PD, and β-thalassemia variants through molecular characterisation in a representative sample of the population from the urban area of Buenaventura, Colombia.

Material and methods: A total of 819 individuals were randomly selected from 12 communities within the city. Molecular analysis was performed using PCR-RFLP and allele-specific PCR. Data were analysed using descriptive statistics, tests of independence, and regression analysis.

Results: Frequencies of 3.1%, 2.2%, 72.2%, 2.1%, 2.8%, and 11% were found for the resistance alleles HbS, HbC, Duffy, β-thalassemia-29, β-thalassemia-88 and G6PD, respectively. In addition, adolescents and young adults (13 to 26 years) presented the highest proportion of resistance genotypes. Likewise, the communities of the insular zone of Buenaventura had the highest proportion of resistance genotypes.

Conclusions: These findings should be considered by public health and disease prevention authorities, as they highlight specific age groups and communities that may be more susceptible to malaria infection. They also identify groups that may contribute to the persistence and potential increase in the prevalence of haemoglobinopathies in the population over time.

Background: Neoadjuvant chemoradiotherapy (nCRT) is essential for treating locally advanced rectal cancer (LARC), however response to nCRT varies, and reliable predictors are lacking.

Methods: This study used whole exome sequencing analysis to investigate genetic differences between tumors highly responsive and non-responsive to nCRT. Five patients with good response and two patients without response to nCRT were used as a discovery set.

Results: The analysis identified 15 InDels and 202 non-synonymous SNVs exclusively present in tumors of non-responders, mainly in genes regulating the cell cycle, adhesion, and migration. In contrast, 9 InDels and 122 non-synonymous SNVs were exclusively present in tumors of good responders, primarily in extracellular matrix remodeling and immunity-related genes. Six variants in transmembrane transporter genes were selected as candidate biomarkers and validated in 33 LARC patients.

Conclusion: The results suggest that SLC16A6 rs7222013 and SLC25A2 rs3749780 may serve as potential predictors of poor nCRT response in LARC patients.

Purpose: The aim of this systematic review is to identify all genome-wide association study (GWAS)-based polygenic risk score (PRS) studies (with different PRS approaches) reported in African ancestry populations diagnosed with any type of cancer. Additionally, this review assessed the role of PRS in advancing precision medicine through its clinical utility across different cancer types in African populations.

Methods: We searched PubMed from January 2009 to April 2023 and included GWAS-based PRS studies for cancer patients of African genetic ancestry.

Results: Among the 33 eligible studies, prostate cancer and breast cancer were the most common types in adults, whereas only one publication reported the risk association of neuroblastoma (a pediatric cancer). The most common PRS approach used was ancestry-specific PRS. Clinical utility of the calculated PRS varies across cancer types, with inconsistent results. Our systematic review found a limited number of PRS studies on cancer patients (adult and pediatric) of African ancestry, and these studies showed less clinical utility compared to those conducted in European ancestry populations.

Conclusion: To make PRS clinically actionable for African ancestry populations, it is crucial to increase the number of large-scale, population-specific GWAS, improve the representation of African-ancestry cohorts, and refine PRS models to better reflect the genetic diversity within African populations.

Background and aims: Sherpa highlanders exhibit remarkable tolerance to hypoxia, most likely due to genetic adaptations shaped by natural selection at high altitude. This study examined the roles of endothelial PAS domain protein 1 (EPAS1) and egl-9 family hypoxia-inducible factor 1 (EGLN1) in the genetic mechanisms underlying this adaptation.

Methods: Blood samples were collected from 56 Sherpa highlanders residing in Namche Bazaar (3440 m) and 25 non-Sherpa lowlanders in Kathmandu (1300 m). Samples were measured for serum erythropoietin (EPO) concentrations, genetic variants of EPAS1 (rs13419896:G>A; rs4953354:A>G) and EGLN1 (rs1435166:G>A; rs2153364:A>G), and mRNA expression levels of the EPAS1 and EGLN1.

Results: Oxygen saturation (SpO₂) was significantly lower in Sherpas at high altitude than in non-Sherpas at low altitude, consistent with a hypoxic state. However, serum EPO concentrations in Sherpas were comparable to those of non-Sherpas, despite the expected hypoxia-driven stimulation of EPO production. Genotyping revealed significantly lower frequencies of the wild-type alleles of EPAS1 and EGLN1 in Sherpas compared with non-Sherpas. These genetic patterns were linked to markedly reduced mRNA expression levels of both genes in Sherpa highlanders.

Conclusion: High-altitude adaptive genetic variants in EPAS1 and EGLN1 are associated with reduced systemic mRNA expression of these genes and a blunted EPO response in Sherpa highlanders, suggesting transcriptional modulation of the hypoxia-induced factor pathway under chronic hypoxia. This attenuated hypoxic response manifests as the tolerance to hypoxia in Sherpa highlanders, enabling Sherpas to adapt to high-altitude hypoxia.

Background: Mitochondrial proteins are encoded by both mitochondrial- and nuclear-encoded genes. Because mitochondrial DNA (mtDNA) is maternally inherited, admixed individuals may have different ancestral sources for their nuclear and mitochondrial genomes. The potential incompatibility between these genomic components may cause suboptimal mitochondrial function and result in energy-related pathologies. This incompatibility, or 'mitonuclear discordance', is defined as the proportion of the nuclear genome not derived from the same ancestral source as the mtDNA.

Methods: Based on this understanding, we hypothesized that increased mitonuclear discordance would be associated with lower mitochondrial copy number and increased risk of gout, type 2 diabetes and chronic kidney disease. We tested this prediction using genomic data from a cohort of 2301 New Zealanders with Polynesian ancestry (Indigenous Māori and Pacific peoples living in Aotearoa New Zealand).

Results: We observed that increased mitonuclear discordance was correlated with a decreased chance of gout (p = 5.08 × 10^-5) and a decreased chance of diagnosis with type 2 diabetes, specifically in individuals having haplogroup B4a1a (p = 4.20 × 10^-9), which was present in 86.0% of the Polynesian study cohort. No significant association was found between mitonuclear discordance and mitochondrial copy number (p = 0.93), risk of chronic kidney disease (p = 0.084) or gout flare frequency (p = 0.53).

Conclusion: Overall, while these results contradicted our hypothesis, they can potentially be explained by a higher prevalence of disease-associated alleles for gout and type 2 diabetes in Polynesian genomes.

Background: Hepatocellular carcinoma (HCC) is a highly aggressive cancer with significant intratumoral heterogeneity, likely contributed by the differentiation of cancer stem-like cells (CSCs) into multiple cancer cell lineages, resulting in therapeutic resistance and increased patient mortality. However, there is limited evidence from patient samples regarding the critical role of CSCs in treatment efficacy and patient outcomes.

Methods: In this study, through the analysis of single-cell transcriptomic data of HCC patient samples, we identify a rare population of cells with cancer stem-like features. Next, we constructed a 12-gene signature that accurately predicts patient survival. Furthermore, based on the expression levels of the 12-gene signature of CSCs, a CAncer stem-like cell Risk Score (CARS) is computed.

Results: The results show that patients with a higher CARS exhibit increased resistance to sorafenib but greater sensitivity to immune checkpoint inhibitors (ICI). The identification of CSCs in the single-cell transcriptome also provides a unique opportunity to study the microenvironmental characteristics of CSCs in HCC. HCC samples with higher CARS show a substantial infiltration of B cells, and the glycoprotein signaling of GRN and PSAP is specifically associated with the crosstalk between B cells and CSCs, rather than other tumor cells.

Conclusion: These findings develop CARS of potential prognostic and predictive value in HCC management.

Background: Neurological disorders affect both the central and peripheral nervous systems, exhibiting broad genetic and clinical variability and posing a significant public health concern. These conditions range from common disorders, such as attention deficit disorder and epilepsy, to rare diseases like intellectual disability (ID) and white matter disorders. Exome sequencing (ES) has emerged as a powerful tool in diagnosing the genetic underpinnings of these disorders. ES demonstrated its feasibility as a cost-effective diagnostic pathway by identifying pertinent diagnostic outcomes in 29.4% of cases and being noticeably more cost-effective than conventional genetic diagnostic techniques.

Methodology: This study investigated the genetic basis of three rare neurological disorders in three unrelated Pakistani families using ES. Each family presents with a distinct syndromic form of ID, associated with bilateral frontoparietal polymicrogyria (BFPP) (Family-1), Li-Ghorbani-Weisz-Hubshman syndrome (LIGOWS) (Family-2), or hypomyelination and congenital cataract (HCC) (Family-3). The functional consequences of the missense variants were investigated using bioinformatic prediction tools to confirm the pathogenicity.

Results: In Family-1 with BFPP, ES identified a novel homozygous missense variant ((NM_001145771.3): c.1579C > T; (NP_001139243.1): p.Pro527Ser) in ADGRG1, predicted to impact protein function. In Family-2 with LIGOWS, a novel homozygous missense variant ((NM_182958.4): c.649A > C; (NP_892003.2): p.Met217Leu) was found in KAT8. In Family-3 with HCC, a novel homozygous nonsense variant ((NM_032581.4): c.722T > G; (NP_115970.2): p.Leu241Ter) was identified in FAM126A, likely resulting in a truncated, nonfunctional protein. Families' structures and segregation analysis confirm disease condition segregating with autosomal recessive mode of inheritance. The functional consequences of the ADGRG1 and KAT8 missense variants were revealed as deleterious using bioinformatic prediction tools.

Conclusions: We have identified novel pathogenic variants in ADGRG1, KAT8, and FAM126A in individuals with rare neurological disorders, thereby expanding the genetic and clinical spectrum of these conditions. This study reports, for the first time, an autosomal recessive inheritance pattern for a KAT8-related disorder, providing new insights into its genetic architecture.

Background: Severe asthenozoospermia, particularly when associated with multiple morphological abnormalities of the flagella (MMAF), represents a genetically influenced disorder, although the precise pathogenic mechanisms remain incompletely characterized.

Methods: In this study, whole-exome sequencing (WES) was performed for 44 asthenoteratozoospermia patients, and 11 pathogenic genes were detected in 20 of them (45.5%). Our investigation focused on CFAP74 variants identified in two unrelated patients: a homozygous c.3532G>A mutation in Patient P43 and novel compound heterozygous variants (c.2452C>T and c.3044T>C), first reported in this study, in Patient P24.

Results: Ultrastructural analyses using scanning and transmission electron microscopy revealed characteristic flagellar defects, including a thinner midpiece, disorganized mitochondrial sheath arrangement and axonemal structural abnormalities. Immunofluorescence analysis demonstrated that CFAP74 localized at the entire flagella of control and proband spermatozoa, indicating these missense variants do not disrupt protein expression or subcellular location. Notably, the P24 couple experienced three failed intracytoplasmic sperm injection (ICSI) attempts prior to achieving successful pregnancy through donor sperm by in vitro fertilization (IVF), highlighting the clinical implications of CFAP74-related fertility impairments.

Conclusion: This study expands the mutational spectrum of CFAP74 and further supports the causality between CFAP74 mutations and male infertility.