Annals of Human Genetics最新文献

Background

The classification of sequence variants is at the core of human genetic diagnostics and is the basis for clinical guidance - incorrectly classified variants may cause great harm to patients and their families.

Methods

We provide an overview of the evolution of ideas and algorithms that have led to the formulation of elaborate classification systems over the last decades, culminating in the ACMG/AMP classification system. Furthermore, we address a still unsolved problem in the clinical translation of DNA analyses: variants of unclear significance (VUS).

Results

Rigorous data sharing and the sub-categorisation of VUS could facilitate a clearer interpretation of VUS.

Conclusion

This review underscores the efforts of the HUGO Education Committee to empower professional—sespecially in resource-limited settings—with the expertise needed for high-quality variant interpretation, fostering equitable access to the transformative potential of genomic medicine.

The recent study by Makay et al. significantly advances our understanding of artificial intelligence (AI)-based tools for evaluating facial dysmorphism, particularly within underrepresented populations such as Central African children. This commentary underscores the importance of integrating AI phenotyping technologies with traditional clinical assessments, emphasizing their complementary roles rather than replacement. The commentary further explores methodological enhancements, including the integration of three-dimensional facial analysis, and highlights the necessity for ongoing validation studies in diverse ethnic cohorts to optimize algorithmic precision and clinical applicability. These refinements are essential for improving dysmorphology evaluations globally, particularly in regions with limited genetic healthcare resources.

Background

Idiopathic pulmonary fibrosis (IPF), the predominant idiopathic interstitial pneumonia, is marked by progressive, irreversible lung damage with a 3-year median survival rate in the elderly. Cardiovascular disease (CVD) is the most common disease in the elderly population and its incidence is increasing all the time, especially in the Asia-Pacific region, coinciding with the rise in global mortality. Despite clinical indications of a link between IPF and CVD, the mechanisms are not well understood. This study applies a bidirectional two-sample Mendelian randomization (MR) approach to explore potential causalities between IPF and CVD.

Methods

Summary data from public genome-wide association study (GWAS) databases for IPF (27,449 participants) and CVD were utilized. Single nucleotide polymorphisms (SNPs) served as instrumental variables in MR analysis, employing inverse variance-weighted (IVW), weighted median (WM), and MR-Egger methods. Heterogeneity was assessed with Cochran's Q test, and sensitivity analyses were conducted using MR-PRESSO.

Results

The IVW analysis revealed no significant associations between genetically predicted IPF and CVD, except for a significant negative association with large artery atherosclerosis stroke and IPF. The WM method supported this inverse relationship. MR-Egger intercept indicated pleiotropy in the link between IPF and heart failure, with no outliers detected by MR-PRESSO. Cochran's Q test showed no significant heterogeneity for the relationships.

Conclusion

The bidirectional MR study suggests a potential negative influence of large artery atherosclerosis stroke on IPF, hinting at a protective role of IPF in stroke incidence. The absence of significant associations with other CVDs and IPF implies a more complex relationship than previously considered. Further research is needed to clarify the intricate connections between IPF and CVD.

Introduction

Southeast Asia (SEA) is a region with enriched human diversity and complex population history. Despite numerous small-scale population genetics studies being carried out, the map of human migration in this landmass remains fragmentary. Notably, the genetic affinities of the Orang Asli from Peninsular Malaysia and other SEA natives have not been comprehensively assessed.

Methods

In this study, publicly available genotypic datasets were gathered and imputed. The genetic relationships and ancestry make-up of 19 SEA native populations, covering Peninsular Malaysia, Indonesia, Papua New Guinea, the Philippines, Vietnam, and Andaman, were comprehended and benchmarked with 14 global populations.

Results

With ∼20 million SNPs coverage, we provided supporting evidence to (i) a possible ancient genetic link between the Andamanese, Papuan and the Philippines and Peninsular Negrito; (ii) gene flow from the ancestors of Andamanese to Papuan, and the Negrito from Peninsular Malaysia and the Philippines; (iii) different genetic structures between the island SEA (iSEA) and mainland (mSEA) populations; (iv) close genetic affinity between the Proto-Malay Seletar with the iSEA populations and (v) close genetic affinity between the Senoi Mah Meri with the Proto-Malays.

Conclusion

To our knowledge, this study reported the highest genomic sequence coverage and the most comprehensive SEA native populations covered thus far. Our results not only have provided strong supporting evidence to the earlier hypothesis, but also novel insights into the genetic diversity of the SEA native populations.

Background

Hereditary spherocytosis (HS) is a chronic non-immune hemolytic anemia caused by congenital defects in the erythrocyte membrane. Gene variations can lead to HS, and the SPTB gene variation is one of them. However, HS with cholangiolithiasis and extremely intrahepatic cholestasis had been rarely discussed as a phenotype caused by SPTB gene variation, and the pathogenic mechanism of this gene variation is still unclear.

Methods

Clinical data were collected, genetic analysis was carried out by high throughput sequencing and Sanger sequencing, and then pathogenic mechanism of gene variation was revealed by Western blot analysis.

Results

Two children were admitted because of severe jaundice and finally confirmed as HS complicated with cholangiolithiasis and severe intrahepatic cholestasis. After conservative treatments, symptoms of cholangiolithiasis and intrahepatic cholestasis relieved. Respectively, two novel heterozygous variations of SPTB gene, (NM_001024858.4: c.493_494insTG, p. Q165fs) and (NM_001024858.4: c.1715delT, p. L572X), were identified in these two families. Western blot analysis revealed that these two pathogenic variations all cause decreased protein expression of β-spectrin.

Conclusions

We have identified two novel SPTB variations in HS with cholangiolithiasis and intrahepatic cholestasis. Moreover, our study enhances current understanding of the phenotype and molecular mechanisms associated with SPTB variation.

Background

To study the genetic characteristics of X-chromosome short tandem repeats (X-STRs) in the Yunnan Yi ethnic minority.

Methods

We analyzed the allele frequencies and forensic parameters for 16 X-STR loci in 432 unrelated Yi individuals (206 males and 226 females) in Chuxiong Yi Autonomous Prefecture, Yunnan Province.

Results

A total of 130 alleles were detected. Except for DXS6800, the other loci are highly polymorphic in the Yunnan Yi ethnicity. The combined values of discrimination for males (PDM) and females (PDF) were 0.999999999968561 and 0.999999999999993, respectively, which can be used for forensic medical identification and genetic studies. On the basis of the results of population comparison, there seems to be a relatively close evolutionary relationship between adjacent populations and different ethnic groups in the same region.

Conclusions

This study contributes to X-chromosome genetic polymorphism data for the Yunnan Yi ethnicity and further enriches reference materials on the Chinese Yi ethnic minority.

Background

Inflammation has been reported to be associated with urethral stricture, whereas rarely any studies have reported the causal relationship between inflammatory cytokines and urethral stricture. We investigated the causal effects between inflammatory cytokines and urethral stricture with Mendelian randomization (MR).

Methods

Genome-wide association study (GWAS) summary statistics on 41 inflammatory cytokines from 8293 Finns and 787 patients with urethral stricture were included for bidirectional MR analysis. The causality between inflammatory cytokines and urethral stricture was estimated using inverse variance weighting (IVW), weighted median, and model selection. Multiple sensitivity analyses (including pleiotropy, heterogeneity, and leave-one-out tests) were performed to evaluate the robustness and dependability of the MR results, followed by Bayesian colocalization, phenotype scanning, and protein–protein interaction (PPI) analysis.

Results

We identified a significant causal relationship between three inflammatory cytokines (granulocyte colony-stimulating factor [GCSF], stem cell growth factor beta [SCGFb], and interleukin-5 [IL5]) and urethral stricture. GCSF (odds ratio [OR] = 4.722, 95% confidence interval [CI] = 1.367–16.303, p = 0.014) and SCGFb (OR = 1.209, 95% CI = 1.06–1.379, p = 0.004) increased the risk of urethral stricture, whereas IL5 decreased the risk of urethral stricture (OR = 0.782, 95% CI = 0.626–0.976, p = 0.029). Reverse MR showed no reverse causality between inflammatory cytokines, with significant causality and urethral stricture. PPI analysis showed that the three inflammatory cytokines interacted with multiple fibrosis-related genes: transforming growth factor beta 1, nitric oxide synthase 2, and C–X–C motif chemokine receptor 3.

Conclusion

Our study demonstrated that the inflammatory cytokines GCSF, SCGFb, and IL5 are significantly associated with urethral stricture, providing valuable insights for the prevention and diagnosis of urethral stricture.