Annals of Human Genetics最新文献

Aggregate tests of rare variants are often employed to identify associated regions compared to sequentially testing each individual variant. When an aggregate test is significant, it is of interest to identify which rare variants are “driving” the association. We recently developed the rare variant influential filtering tool (RIFT) to identify influential rare variants and showed RIFT had higher true positive rates compared to other published methods. Here we use importance measures from the standard random forest (RF) and variable importance weighted RF (vi-RF) to identify influential variants. For very rare variants (minor allele frequency [MAF] < 0.001), the vi-RF:Accuracy method had the highest median true positive rate (TPR = 0.24; interquartile range [IQR]: 0.13, 0.42) followed by the RF:Accuracy method (TPR = 0.16; IQR: 0.07, 0.33) and both were superior to RIFT (TPR = 0.05; IQR: 0.02, 0.15). Among uncommon variants (0.001 < MAF < 0.03), the RF methods had higher true positive rates than RIFT while observing comparable false positive rates. Finally, we applied the RF methods to a targeted resequencing study in idiopathic pulmonary fibrosis (IPF), in which the vi-RF approach identified eight and seven variants in TERT and FAM13A, respectively. In summary, the vi-RF provides an improved, objective approach to identifying influential variants following a significant aggregate test. We have expanded our previously developed R package RIFT to include the random forest methods.

BRCA1 variants are extensively associated with increased risk of breast cancer. Early detection and screening of variants is still rare in developing countries. Here, we investigated six BRCA1 variants in 300 subjects from Pakistani population using tetra amplification-refractory mutation system (T-ARMS) PCR. Our results indicate significant association of BRCA1 variants rs8176237 (AA; OR 8.2, 95% CI 3.02–22.64, p < 0.0001), rs1060915 (CC; OR 4.29, 95% CI 1.94–9.48, p = 0.0003), and rs799912 (TT; OR 3.16, 95% CI 1.44–6.94, p = 0.004) with up to 8-fold increased odds of breast cancer under recessive model. Furthermore, BRCA1 haplotypes AGCACG and AGCCCT were associated with up to 18% breast cancer cases (p < 0.05). Additionally, we found association of these variants with up to 11-fold increased odds of benign breast tumors. Linkage disequilibrium (LD) block-wise analysis revealed haplotypes GCAC and ATAC were associated with significantly increased risk. To our knowledge, this is the first study that identifies the association of these BRCA1 variants with breast tumors in Pakistani population. In conclusion, BRCA1 variants investigated in the present study are associated with high odds of benign- and malignant breast tumors. Studies with bigger sample size may help early detection and screening to reduce the odds of breast cancer.

During the colonial period in South America, many autochthonous populations were affected by relocation by European missionary reductions and other factors that impacted and reconfigured their genetic makeup. Presently, the descendants of some “reduced” and other isolated groups are distributed in the Amazonian areas of Peru, Bolivia, and Brazil, and among them, speakers of Takanan and Panoan languages. Based on linguistics, these peoples should be closely related, but so far no DNA comparison studies have been conducted to corroborate a genetic relationship. To clarify these questions, we used a set of 15 short tandem repeats of the non-recombining part of the Y-chromosome (Y-STRs) and mitochondrial DNA (mtDNA) control region sequence data. Paternal line comparisons showed the Takanan-speaking peoples from Peru and Bolivia descended from recent common ancestors; one group was related to Arawakan, Jivaroan, and Cocama and the other to Panoan speakers, consistent with linguistics. Also, a genetic affinity for maternal lines was observed between some Takanan speakers and individuals who spoke different Amazonian languages. Our results supported a shared ancestry of Takanan, Panoan, Cocama, and Jivaroan-speaking communities who appeared to be related to each other and came likely from an early Arawak expansion in the western Amazonia of South America.

Introduction: Massively parallel sequencing (MPS) techniques have made a major impact on the identification of the genetic basis of inherited kidney diseases such as the ciliopathy autosomal dominant polycystic kidney disease (ADPKD). Great care must be taken when analysing MPS data in isolation from accurate phenotypic information, as this can cause misdiagnosis. Methods: Here, we describe a family trio, recruited to the Genomics England 100,000 Genomes Project, labelled as having cystic kidney disease, who were genetically unsolved following routine data analysis pipelines. We performed a bespoke reanalysis of Whole Genome Sequencing (WGS) data and coupled this with revised phenotypic data and targeted PCR and Sanger sequencing to provide a precise molecular genetic diagnosis. Results: We detected a heterozygous PKD1 frameshift variant within the WGS data which segregated with the redefined ADPKD phenotypes. An additional heterozygous exon deletion in ALG8 was also found in affected and unaffected individuals, but its precise clinical significance remains unclear. Conclusion: This case illustrates that reanalysis of WGS data in unsolved cases of cystic kidney disease is valuable. Clinical phenotypes must be reassessed as these may have been incorrectly recorded and evolve over time. Undertaking additional studies including genotype-phenotype correlation in wider family members provides useful diagnostic information.

Introduction

Observational studies have shown that body mass index (BMI) and waist-to-hip ratio (WHR) are both inversely associated with lung function, as assessed by forced vital capacity (FVC) and forced expiratory volume in 1 s (FEV1). However, observational data are susceptible to confounding and reverse causation.

Methods

We selected genetic instruments based on their relevant large-scale genome-wide association studies. Summary statistics of lung function and asthma came from the UK Biobank and SpiroMeta Consortium meta-analysis (n = 400,102). After examining pleiotropy and removing outliers, we applied inverse-variance weighting to estimate the causal association of BMI and BMI-adjusted WHR (WHRadjBMI) with FVC, FEV1, FEV1/FVC, and asthma. Sensitivity analyses were performed using weighted median, MR-Egger, and MRlap methods.

Results

We found that BMI was inversely associated with FVC (effect estimate, −0.167; 95% confidence interval (CI), −0.203 to −0.130) and FEV1 (effect estimate, −0.111; 95%CI, −0.149 to −0.074). Higher BMI was associated with higher FEV1/FVC (effect estimate, 0.079; 95%CI, 0.049 to 0.110) but was not significantly associated with asthma. WHRadjBMI was inversely associated with FVC (effect estimate, −0.132; 95%CI, −0.180 to −0.084) but has no significant association with FEV1. Higher WHR was associated with higher FEV1/FVC (effect estimate, 0.181; 95%CI, 0.130 to 0.232) and with increased risk of asthma (effect estimate, 0.027; 95%CI, 0.001 to 0.053).

Conclusion

We found significant evidence that increased BMI is suggested to be causally related to decreased FVC and FEV1, and increased BMI-adjusted WHR could lead to lower FVC value and higher risk of asthma. Higher BMI and BMI-adjusted WHR were suggested to be causally associated with higher FEV1/FVC.

Biallelic CC2D2A variants are associated with a wide range of neurodevelopmental disorders including Meckel syndrome. Here we report a Japanese girl with Meckel syndrome harboring a pathogenic deep intronic variant (NM_001378615.1:c.1149+3569A>G) and an exonic LINE-1 insertion, which was predicted to cause aberrant splicing by SpliceAI and was detected by TEMP2 program, respectively. RNA analysis using urine-derived cells (UDCs) showed retention of 149-bp intronic sequences, leading to frameshift. Immunoblotting showed marked reduction of CC2D2A protein in the patient. Our report demonstrated that utilization of transposon detection tool and functional analysis using UDCs will increase diagnostic yield of genome sequencing.

Introduction: Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis. Methods: We describe a detailed clinical and genetic characterization of three siblings with CSA. Results: Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in SLC25A38 gene NM_017875.2:c.559C > T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in GMPPB gene NM_013334.3:c.458C > T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement. Conclusion: This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations.

Objective

The objective of this study was to investigate the pathogenesis and inheritance pattern of a Chinese Han family with hereditary spastic paraplegia and to retrospectively analyze the characteristics of KIF1A gene variants and related clinical manifestations.

Methods

High-throughput whole-exome sequencing was performed on members of a Chinese Han family with a clinical diagnosis of hereditary spastic paraplegia, and the sequencing results were validated by Sanger sequencing. Deep high-throughput sequencing was performed on subjects with suspected mosaic variants. The previously reported pathogenic variant loci of the KIF1A gene with complete data were collected, and the clinical manifestations and characteristics of the pathogenic KIF1A gene variant were analyzed.

Results

A pathogenic heterozygous variant located in the neck coil of the KIF1A gene (c.1139G>C, p.Arg380Pro) was identified in the proband and four additional members of the family. It was derived from the de novo low-frequency somatic-gonadal mosaicism of the proband's grandmother and had a rate of 10.95%.

Interpretation

This study helps us to better understand the pathogenic mode and characteristics of mosaic variants, and to understand the location and clinical characteristics of pathogenic variants in KIF1A.