Annals of Human Genetics最新文献

Backgroud

Tripartite motif containing 5α protein is a factor contributing to intracellular defense mechanisms against human immunodeficiency virus-1 (HIV-1) infection. The studies of TRIM5 variants effects on the risk of HIV-1 infection and the clinical course of disease provided inconclusive results in different ethnic groups. The aim of this study was to investigate the influence of TRIM5 variants on susceptibility to HIV-1 infection and clinical parameters among Polish HIV-1-infected patients.

Materials & Methods

In our study, we investigated 301 HIV-1-infected patients and 186 age-matched seronegative controls. Seven variants of the TRIM5 gene (rs7127617, rs3824949, rs3740996, rs11601507, rs10838525, rs11038628, and rs28381981) were genotyped using both sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) techniques.

Results and Conclusions

The frequencies of rs7127617 TT genotype and T allele occurrence were lower in HIV-1-infected subjects compared to controls (0.14 vs. 0.26 for T/T genotype and 0.45 vs. 0.54 for T allele), suggesting their possible protective effect (p = 0.005 and p = 0.007, respectively). Heterozygosity and presence of the T allele at rs3740996 were enriched in controls compared to HIV-1-infected group (0.19 vs. 0.12 for C/T genotype and 0.11 vs. 0.07 for T allele; p = 0.03 and p = 0.02, respectively). Moreover, rs3824949 CC genotype carriers had a lower viral load than patients bearing rs3824949 GG/CG genotypes (4.0 vs. 4.6 log copies/mL; p = 0.049); however, none of the variants affected CD4⁺ cell count. In conclusion, our data confirm the role of TRIM5 variants in the HIV-1 transmission and the clinical course of HIV-1 infection. The presence of rs7127617 TT genotype and T allele seems to protect against HIV-1 transmission in examined population.

Purpose

Currently, several genetic variants in ERα gene (rs2234693 and rs9340799), ERβ gene (rs1256049 and rs4986938), KISS1 gene (rs4889, rs1132506 and rs5780218), LIN28B gene (rs314263, rs314276 and rs314280), and MKRN3 gene (rs2239669) have been repeatedly explored for their contribution to precocious puberty (PP) susceptibility. However, the results remain conflicting rather than conclusive. We here performed a meta-analysis to identify the real susceptibility genetic variants for PP.

Methods

After screening by inclusion criteria, 20 related studies were finally included in this meta-analysis. The odds ratios and 95% confidence intervals were calculated to assess the strength of association. Sensitive analysis, publication bias, and trial sequential analysis (TSA) were performed to evaluate the stability and reliability of results.

Results

Rs2234693, rs9340799, and rs1256049 were significantly associated with PP susceptibility (p < 0.0084). Stratified analysis according to ethnicity showed that rs2234693 and rs9340799 were significantly associated with PP susceptibility in Asian and Chinese populations. Stratified analysis according to PP subtype showed that rs2234693 and rs9340799 were significantly associated with idiopathic central PP susceptibility in Asian and Chinese populations (p < 0.0084). The results of publication bias, sensitivity analysis, and TSA provided solid evidence for the association between these three variants and PP susceptibility.

Conclusions

Rs2234693 and rs9340799 in ERα gene and rs1256049 in ERβ gene may serve as susceptive factors for PP development. The present finding should be confirmed in replication studies and reinforced in functional studies, which will ultimately improve the feasibility of the application of these three PP-susceptible loci in clinical practice.

Introduction: Joubert syndrome (JS) arises from defects of primary cilia resulting in potential malformations of the brain, kidneys, eyes, liver, and limbs. Several of the 35+ genes associated with JS have recognized genotype/phenotype correlations, but most genes have not had enough reported individuals to draw meaningful conclusions.

Methods: A PubMed literature review identified 688 individuals with JS across 32 genes and 112 publications to bolster known genotype/phenotype relationships and identify new correlations.

All included patients had the “molar tooth sign” and a confirmed genetic diagnosis. Individuals were categorized by age, ethnicity, sex and the presence of developmental disability/intellectual disability, hypotonia, abnormal eye movements, ataxia, visual impairment, renal impairment, polydactyly, and liver abnormalities.

Results: Most genes demonstrated unique phenotypic profiles. Grouping proteins based on physiologic interactions established stronger phenotypic relationships that reflect known ciliary pathophysiology. Age-stratified data demonstrated that end-organ disease is progressive in JS. Most genes demonstrated a significant skew towards having variants with either residual protein function or no residual protein function.

Conclusion: This cohort demonstrates that clinically meaningful genotype/phenotype relationships exist within most JS-related genes and can be referenced to allow for more personalized clinical care.

Introduction

Prostate cancer is one of the most common cancer types in males and rs12621278:A > G has been suggested to be associated with this disease by previous genome-wide association studies. One thousand genomes project data analysis indicated that rs12621278:A > G is within two long-core haplotypes. However, the origin, causal variant(s), and molecular function of these haplotypes were remaining unclear.

Materials and Methods

Population genetics analysis and functional genomics work was performed for this locus.

Results

Phylogeny analysis verified that the rare haplotype is derived from Neanderthal introgression. Genome annotation suggested that three genetic variants in the core haplotypes, rs116108611:G > A, rs139972066:AAAAAAAA > AAAAAAAAA, and rs3835124:ATTTATT > ATT, are located in functional regions. Luciferase assay indicated that rs139972066:AAAAAAAA > AAAAAAAAA and rs116108611:G > A are not able to alter ITGA6 (integrin alpha 6) and ITGA6 antisense RNA 1 expression, respectively. In contrast, rs3835124:ATTTATT > ATT can significantly influence PDK1 (pyruvate dehydrogenase kinase 1) expression, which was verified by expression quantitative trait locus analysis. This genetic variant can alter transcription factor cut like homeobox 1 interaction efficiency. The introgressed haplotype was observed to be subject to positive selection in East Asian populations. The molecular function of the haplotype suggested that Neanderthal should be with lower PDK1 expression and further different energy homeostasis from modern human.

Conclusion

This study provided new insight into the contribution of Neanderthal introgression to human phenotypes.

Introduction

Next generation sequencing technology has greatly reduced the cost and time required for sequencing a genome. An approach that is rapidly being adopted as an alternative method for CNV analysis is the low-pass whole genome sequencing (LP-WGS). Here, we evaluated the performance of LP-WGS to detect copy number variants (CNVs) in clinical cytogenetics.

Materials and Methods

DNA samples with known CNVs detected by chromosomal microarray analyses (CMA) were selected for comparison and used as positive controls; our panel included 44 DNA samples (12 prenatal and 32 postnatal), comprising a total of 55 chromosome imbalances. The selected cases were chosen to provide a wide range of clinically relevant CNVs, the vast majority being associated with intellectual disability or recognizable syndromes. The chromosome imbalances ranged in size from 75 kb to 90.3 Mb, including aneuploidies and two cases of mosaicism.

Results

All CNVs were successfully detected by LP-WGS, showing a high level of consistency and robust performance of the sequencing method. Notably, the size of chromosome imbalances detected by CMA and LP-WGS were compatible between the two different platforms, which indicates that the resolution and sensitivity of the LP-WGS approach are at least similar to those provided by CMA.

Discussion

Our data show the potential use of LP-WGS to detect CNVs in clinical diagnosis and confirm the method as an alternative for chromosome imbalances detection. The diagnostic effectiveness and feasibility of LP-WGS, in this technical validation study, were evidenced by a clinically representative dataset of CNVs that allowed a systematic assessment of the detection power and the accuracy of the sequencing approach. Further, since the software used in this study is commercially available, the method can easily be tested and implemented in a routine diagnostic setting.

Introduction

Next-generation sequencing helps clinicians diagnose patients with suspected genetic disorders. The current study aimed to investigate the diagnostic yield and clinical utility of prospective whole-exome sequencing (WES) in rare diseases.

Methods

WES was performed in 92 patients who presented with clinical symptoms suggestive of genetic disorders. The WES data were analyzed using an in-house developed software. The patients’ phenotypic characteristics were classified according to the human phenotype ontology.

Results

WES detected 64 variants, 13 were classified as pathogenic, 26 as likely pathogenic, and 25 as variants of uncertain significance. In 57 patients with these variants, 30 were identified as causal variants. The diagnostic yield was higher in patients with abnormalities in joint mobility and skin morphology than in those with cerebellar hypoplasia/atrophy, epilepsy, global developmental delay, dysmorphic features/facial dysmorphisms, and chronic kidney disease/abnormal renal morphology.

Conclusion

In this study, a WES-based variant interpretation system was employed to provide a definitive diagnosis for 28.3% of the patients suspected of having genetic disorders. WES is particularly useful for diagnosing rare diseases with symptoms that affect more than one system, when targeted genetic panels are difficult to employ.

Introduction

Population stratification (PS) is a major source of confounding in population-based genetic association studies of quantitative traits. Principal component regression (PCR) and linear mixed model (LMM) are two commonly used approaches to account for PS in association studies. Previous studies have shown that LMM can be interpreted as including all principal components (PCs) as random-effect covariates. However, including all PCs in LMM may dilute the influence of relevant PCs in some scenarios, while including only a few preselected PCs in PCR may fail to fully capture the genetic diversity.

Materials and methods

To address these shortcomings, we introduce Bayestrat—a method to detect associated variants with PS correction under the Bayesian LASSO framework. To adjust for PS, Bayestrat accommodates a large number of PCs and utilizes appropriate shrinkage priors to shrink the effects of nonassociated PCs.

Results

Simulation results show that Bayestrat consistently controls type I error rates and achieves higher power compared to its non-shrinkage counterparts, especially when the number of PCs included in the model is large. As a demonstration of the utility of Bayestrat, we apply it to the Multi-Ethnic Study of Atherosclerosis (MESA). Variants and genes associated with serum triglyceride or HDL cholesterol are identified in our analyses.

Discussion

The automatic and self-selection features of Bayestrat make it particularly suited in situations with complex underlying PS scenarios, where it is unknown a priori which PCs are potential confounders, yet the number that needs to be considered could be large in order to fully account for PS.