ACGS Best Practice Guidelines for Variant Classification in Rare Disease 2020, a supplementary practical guidelines, is based on the Standards and Guidelines for the Interpretation of Sequence Variations issued by the American Society for Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP) in 2015 by the British Medical Genetics Society under the Clinical Genomics Society (ACGS), and has integrated the detailed rules of standards developed by the ClinGen Sequence Variant Interpretation (SVI) Working Group by 2020. The further development of the ACMG/AMP guidelines is currently undertaken by the ClinGen SVI working group in the United States, which focuses on the classification of high penetrance and protein coding variants. ClinGen has established many expert panels on variants for specific diseases which required various evidence thresholds and is currently developing disease/gene specific guidelines. The British Medical Genetics Society has collected and integrated information on the guidelines for sequence variation classification and their extended rules, forming its own "2020 ACGS Best Practice Guidelines for Rare Disease Variation Classification" and is regularly updating it. The author has translated and summarized it for the reference of Chinese Medical Genetics Practitioners.
Humans ; Genetic Testing ; Genetic Variation ; Genome, Human ; Rare Diseases/genetics* ; China

Copy number variants (CNVs) are common causes of human genetic diseases. CNVs detection has become a routine component of genetic testing, especially for pediatric neurodevelopmental disorders, multiple congenital abnormalities, prenatal evaluation of fetuses with structural anomalies detected by ultrasound. Although the technologies for CNVs detection are continuously improving, the interpretation is still challenging, with significant discordance across different laboratories. In 2020, the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen) developed a guideline for the interpreting and reporting of constitutional copy number variants, which introduced a quantitative, evidence-based scoring framework. Here, we detailed the key points of interpreting the copy number gain based on the guideline, used six examples of different categories to illuminate the scoring process and principles. We encourage a professional understanding and application of this guideline for the detected copy number gains in China in order to further improve the clinical evaluation accuracy and consistency across different laboratories.
Child ; DNA Copy Number Variations ; Female ; Genetic Testing ; Genetics, Medical ; Genome, Human/genetics* ; Genomics ; Humans ; Pregnancy ; United States

As next-generation sequencing (NGS) technology has become widely used to identify genetic causal variants for various diseases and traits, a number of packages for checking NGS data quality have sprung up in public domains. In addition to the quality of sequencing data, sample quality issues, such as gender mismatch, abnormal inbreeding coefficient, cryptic relatedness, and population outliers, can also have fundamental impact on downstream analysis. However, there is a lack of tools specialized in identifying problematic samples from NGS data, often due to the limitation of sample size and variant counts. We developed SeqSQC, a Bioconductor package, to automate and accelerate sample cleaning in NGS data of any scale. SeqSQC is designed for efficient data storage and access, and equipped with interactive plots for intuitive data visualization to expedite the identification of problematic samples. SeqSQC is available at http://bioconductor.org/packages/SeqSQC.
Breast Neoplasms ; genetics ; Cohort Studies ; Continental Population Groups ; genetics ; Female ; Genome, Human ; High-Throughput Nucleotide Sequencing ; methods ; standards ; Humans ; Software ; Whole Exome Sequencing

Consensus ; Genetic Diseases, Inborn ; diagnosis ; genetics ; Genome, Human ; genetics ; High-Throughput Nucleotide Sequencing ; Humans ; Practice Guidelines as Topic ; Sequence Analysis, DNA ; Whole Genome Sequencing

To further enrich the genetic data of the Chinese Xinjiang Mongolian group, the genetic distribution and forensic parameters of 19 autosomal short tandem repeats (STRs) were investigated. Altogether, 249 alleles were observed in these 19 STRs. The mean values of the polymorphism information content (PIC), match probability (MP), discrimination power (DP), and probability of exclusion (PE) for these 19 STRs were 0.7775, 0.0699, 0.9301, and 0.6085, respectively. Additionally, the cumulative DP and PE values obtained in the Mongolian group were 0.999 999 999 999 999 999 999 995 67 and 0.999 999 992 163, respectively. Furthermore, population genetic analysis of the Mongolian group and 20 published populations was conducted based on the population data of 15 overlapping STRs. Genetic distances indicated that the Mongolian group had closer genetic similarities with the Uyghur, Xibe, and other Chinese populations rather than the other continental populations. Multidimensional scaling analysis further revealed that the Mongolian group possessed similar genetic distributions as most Chinese populations. To sum it all up, these STRs could be used as an extremely efficient tool for forensic applications in the Xinjiang Mongolian group.
Alleles ; Asian People/genetics* ; China ; DNA Fingerprinting ; Databases, Genetic ; Ethnicity/genetics* ; Gene Frequency ; Genetic Markers ; Genetics, Population ; Genome, Human ; Humans ; Linkage Disequilibrium ; Microsatellite Repeats ; Mongolia ; Polymorphism, Genetic ; Principal Component Analysis ; Probability ; Software

OBJECTIVE: This study aimed to investigate DNA sequences that are substantially homologous to the corresponding RNA sequence sections of the hepatitis C virus (HCV). These DNA sequences are present in the whole DNA extracted from peripheral blood mononuclear cells (PBMCs) of HCV-negative subjects. We presumed that these experimentally proven 5'-noncoding region (5'-NCR) homologous DNA sequences could be contained in the extrachromosomal circular DNA (eccDNA) fraction as part of the whole cellular DNA. METHODS: Home-made polymerase chain reaction (PCR) with whole cellular and isolated eccDNA, nucleotide basic local alignment search tool (BLASTn) alignments, and tests for patterns of methylation in selected sequence sections were performed. RESULTS: The PCR tests revealed DNA sequences of up to 320 bp that broadly matched the corresponding sequence sections of known HCV genotypes. In contrast, BLASTn alignment searches of published HCV 5'-NCR sequences with human genome databases revealed only sequence segments of up to 36 bp of the 5'-NCR. The composition of these sequences shows missing base pairs, base pair mismatches as well as complete homology with HCV reference sequences. These short sequence sections are present in numerous copies on both the same and different chromosomes. The selected sequence region within the DNA sequences of the 5'-NCR revealed a broad diversity of individual patterns of methylation. CONCLUSIONS The experimental results confirm our assumption that parts of the HCV 5'-NCR genomic RNA sequences are present at the DNA level in the eccDNA fraction of PBMCs. The tests for methylation patterns therein revealed individual methylomes which could represent an epigenetic feature. The respective sequence section might be subject to genetic regulation.
Computational Biology ; DNA Methylation ; DNA, Circular/genetics* ; DNA, Viral/genetics* ; Genome, Human ; Genomics ; Genotype ; Hepacivirus/genetics* ; Hepatitis C/virology* ; Humans ; Leukocytes, Mononuclear/virology* ; Polymerase Chain Reaction ; RNA, Viral/genetics* ; Sequence Alignment

Adult ; Azoospermia/pathology* ; Carbonic Anhydrases/genetics* ; Congenital Abnormalities/genetics* ; Epithelial Sodium Channels/genetics* ; Gene Expression Regulation/genetics* ; Genome, Human ; Humans ; Infertility, Male/genetics* ; Male ; Male Urogenital Diseases/genetics* ; Mutation ; Vas Deferens/abnormalities*

The microbiome, which has been defined as ‘the ecological community of commensal, symbiotic and pathogenic microorganisms that share our body space, may be distinguished from the microbiota as it includes the collective genomes. An increasing level of evidence reveals that the human microbiome plays a major role in health. For this reason, it is often referred to as the ‘forgotten organ.’ All surfaces of the human body that are exposed to the environment are colonized, including skin, respiratory system, urogenital tract and gastrointestinal (GI) tract, totaling at least 100 trillion microbial cells. The known roles of the GI microbiome include metabolic functions, synthesis functions, and immune roles. Recent studies indicate that the human gut microbiome plays a significant role in health and disease. Dysbiosis, defined as a pathological imbalance in a microbial community, is becoming increasingly appreciated as a ‘central environmental factor’ that is both associated with complex phenotypes and affected by host genetics, diet, and antibiotic use. More recently, a link has been established between the dysmetabolism of bile acids (BAs) in the gut and the gut-liver axis, and this relationship with the microbiome has been highlighted. This review summarizes the microbiome of the hepatobiliary system and how microbiome is related to diseases of the liver and biliary tract.
Bile Acids and Salts ; Biliary Tract ; Biota ; Colon ; Diet ; Dysbiosis ; Gallbladder ; Gastrointestinal Microbiome ; Genetics ; Genome ; Human Body ; Humans ; Liver ; Microbiota* ; Pancreas ; Phenotype ; Respiratory System ; Skin

Lung squamous cell carcinoma (LUSC) causes approximately 400 000 deaths each year worldwide. The occurrence of LUSC is attributed to exposure to cigarette smoke, which induces the development of numerous genomic abnormalities. However, few studies have investigated the genomic variations that occur only in normal tissues that have been similarly exposed to tobacco smoke as tumor tissues. In this study, we sequenced the whole genomes of three normal lung tissue samples and their paired adjacent squamous cell carcinomas.We then called genomic variations specific to the normal lung tissues through filtering the genomic sequence of the normal lung tissues against that of the paired tumors, the reference human genome, the dbSNP138 common germline variants, and the variations derived from sequencing artifacts. To expand these observations, the whole exome sequences of 478 counterpart normal controls (CNCs) and paired LUSCs of The Cancer Genome Atlas (TCGA) dataset were analyzed. Sixteen genomic variations were called in the three normal lung tissues. These variations were confirmed by Sanger capillary sequencing. A mean of 0.5661 exonic variations/Mb and 7.7887 altered genes per sample were identified in the CNC genome sequences of TCGA. In these CNCs, C:G→T:A transitions, which are the genomic signatures of tobacco carcinogen N-methyl-N-nitro-N-nitrosoguanidine, were the predominant nucleotide changes. Twenty five genes in CNCs had a variation rate that exceeded 2%, including ARSD (18.62%), MUC4 (8.79%), and RBMX (7.11%). CNC variations in CTAGE5 and USP17L7 were associated with the poor prognosis of patients with LUSC. Our results uncovered previously unreported genomic variations in CNCs, rather than LUSCs, that may be involved in the development of LUSC.
Adult ; Aged ; Aged, 80 and over ; Biomarkers, Tumor ; genetics ; Carcinoma, Squamous Cell ; genetics ; Case-Control Studies ; Female ; Genome, Human ; Genomic Structural Variation ; Humans ; Lung Neoplasms ; genetics ; Male ; Middle Aged ; Mutation

Sex differences are widely observed under various circumstances ranging from physiological processes to therapeutic responses, and a myriad of sex-biased genes have been identified. In recent years, transcriptomic datasets of microRNAs (miRNAs), an important class of non-coding RNAs, become increasingly accessible. However, comprehensive analysis of sex difference in miRNA expression has not been performed. Here, we identified the differentially-expressed miRNAs between males and females by examining the transcriptomic datasets available in public databases and conducted a systemic analysis of their biological characteristics. Consequently, we identified 73 female-biased miRNAs (FmiRs) and 163 male-biased miRNAs (MmiRs) across four tissues including brain, colorectal mucosa, peripheral blood, and cord blood. Our results suggest that compared to FmiRs, MmiRs tend to be clustered in the human genome and exhibit higher evolutionary rate, higher expression tissue specificity, and lower disease spectrum width. In addition, functional enrichment analysis of miRNAs show that FmiR genes are significantly associated with metabolism process and cell cycle process, whereas MmiR genes tend to be enriched for functions like histone modification and circadian rhythm. In all, the identification and analysis of sex-biased miRNAs together could provide new insights into the biological differences between females and males and facilitate the exploration of sex-biased disease susceptibility and therapy.
Biological Evolution ; Female ; Genome, Human ; Humans ; Male ; MicroRNAs ; blood ; genetics ; Organ Specificity ; Sex Characteristics ; Transcriptome