Human Genome Variation最新文献

The human Major Histocompatibility Complex (MHC) or Human Leukocyte Antigen (HLA) super-locus is a highly polymorphic genomic region that encodes more than 140 coding genes including the transplantation and immune regulatory molecules. It receives special attention for genetic investigation because of its important role in the regulation of innate and adaptive immune responses and its strong association with numerous infectious and/or autoimmune diseases. In recent years, MHC genotyping and haplotyping using Sanger sequencing and next-generation sequencing (NGS) methods have produced many hundreds of genomic sequences of the HLA super-locus for comparative studies of the genetic architecture and diversity between the same and different haplotypes. In this special issue on 'The Current Landscape of HLA Genomics and Genetics', we provide a short review of some of the recent analytical developments used to investigate the SNP polymorphisms, structural variants (indels), transcription and haplotypes of the HLA super-locus. This review highlights the importance of using reference cell-lines, population studies, and NGS methods to improve and update our understanding of the mechanisms, architectural structures and combinations of human MHC genomic alleles (SNPs and indels) that better define and characterise haplotypes and their association with various phenotypes and diseases.

Accurate genotype imputation requires large-scale reference panel datasets. When conducting genotype imputation on the Japanese population, researchers can use such datasets under collaborative studies or controlled access conditions in public databases. We developed the NBDC-DDBJ imputation server, which securely provides users with a web user interface to execute genotype imputation on the server. Our benchmarking analysis showed that the accuracy of genotype imputation was improved by leveraging controlled access datasets to increase the number of haplotypes available for analysis compared to using publicly available reference panels such as the 1000 Genomes Project. The NBDC-DDBJ imputation server facilitates the use of controlled access datasets for accurate genotype imputation.

This review article describes the current status of data archiving and computational infrastructure in the field of genomic medicine, focusing primarily on the situation in Japan. I begin by introducing the status of supercomputer operations in Japan, where a high-performance computing infrastructure (HPCI) is operated to meet the diverse computational needs of science in general. Since this HPCI consists of supercomputers of various architectures located across the nation connected via a high-speed network, including supercomputers specialized in genome science, the status of its response to the explosive increase in genomic data, including the International Nucleotide Sequence Database Collaboration (INSDC) data archive, is explored. Separately, since it is clear that the use of commercial cloud computing environments needs to be promoted, both in light of the rapid increase in computing demands and to support international data sharing and international data analysis projects, I explain how the Japanese government has established a series of guidelines for the use of cloud computing based on its cybersecurity strategy and has begun to build a government cloud for government agencies. I will also carefully consider several other issues of user concern. Finally, I will show how Japan's major cloud computing infrastructure is currently evolving toward a multicloud and hybrid cloud configuration.

Otopalatodigital spectrum disorder (OPDSD) is characterized by variable phenotypes, including skeletal dysplasia, and is caused by pathogenic variants in filamin A-encoding FLNA. FLNA variants associated with lethal OPDSD primarily alter the CH2 subdomain of the ABD of FLNA. Herein, we report a novel FLNA mutation in a fetus with severe skeletal dysplasia in a pregnant multigravida female with a history of repeated miscarriages and terminations.

TogoVar ( https://togovar.org ) is a database that integrates allele frequencies derived from Japanese populations and provides annotations for variant interpretation. First, a scheme to reanalyze individual-level genome sequence data deposited in the Japanese Genotype-phenotype Archive (JGA), a controlled-access database, was established to make allele frequencies publicly available. As more Japanese individual-level genome sequence data are deposited in JGA, the sample size employed in TogoVar is expected to increase, contributing to genetic study as reference data for Japanese populations. Second, public datasets of Japanese and non-Japanese populations were integrated into TogoVar to easily compare allele frequencies in Japanese and other populations. Each variant detected in Japanese populations was assigned a TogoVar ID as a permanent identifier. Third, these variants were annotated with molecular consequence, pathogenicity, and literature information for interpreting and prioritizing variants. Here, we introduce the newly developed TogoVar database that compares allele frequencies among Japanese and non-Japanese populations and describes the integrated annotations.

Intellectual developmental disorder with dysmorphic facies, speech delay, and T-cell abnormalities (MIM # 618092) is a congenital disorder derived from pathogenic variants of the B-cell leukemia/lymphoma 11B gene (BCL11B). Several variants have been reported to date. Here, through comprehensive genomic analysis, a novel BCL11B truncation variant, NM_138576.4(BCL11B_v001): c.2439_2452dup [p.(His818Argfs*31)], was identified in a Japanese male patient with developmental delay, distinctive features, and early craniosynostosis.

Familial renal glucosuria (FRG) is characterized by persistent glucosuria despite normal blood glucose levels in the absence of overt tubular dysfunction. SGLT2 is a sodium-glucose cotransporter expressed in the proximal tubule; loss-of-function variants in SLC5A2 are the primary cause of FRG. Heterozygous variants have rarely been reported in Japanese individuals. Here, we identified a novel SLC5A2 heterozygous variant, c.1348G>T: p.Gly450Trp, in a Japanese family comprising two children and their father.

Sotos syndrome is usually caused by haploinsufficiency of NSD1; it is characterized by overgrowth, craniofacial features, and learning disabilities. We describe a boy with Sotos syndrome caused by a splicing variant (c.4378+5G>A). The clinical manifestations included severe connective tissue involvement, including joint hypermobility, progressive scoliosis, pectus deformity, and skin hyperextensibility; no overgrowth was observed.

Achondrogenesis type II (ACG2) is a lethal skeletal disorder caused by pathogenic variants in COL2A1. We present a fetus with cystic hygroma and severe shortening of the limbs at 14 weeks of gestation. We performed postnatal genetic analysis of the parents and fetus to diagnose the disease. A novel missense variant of COL2A1 [NM_001844.5: c.2987G>A, (p. Gly996Asp)] was identified, which led to the ACG2 diagnosis.