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简介：AbstractHidradenitis suppurativa (HS) is a chronic, inflammatory skin condition that poses a significant diagnostic and therapeutic challenge for clinicians, as the underlying etiology and pathogenesis remains unclear. The host of genetic mutations and immune dysfunction has been identified to be involved in the pathogenesis of HS during recent years. These genetic defects, including monogenetic mutations altering subunits of γ-secretase, a protease that functions through Notch signaling to maintain skin appendages, promote epithelial stability, suppress/terminate innate immune responses (ie, Toll-receptors), further have the propensity to induce aberrant cytokine responses that create to a proinflammatory environment, consequently induce hyperkeratosis and promote expression of pro-inflammatory, locally destructive matrix metalloproteinases. Cytokine-driven inflammation propagates the disease state of HS and contributes to the formation of painful subcutaneous nodules, abscesses, and eventually, fistulas and draining sinus tracts. A closer look at genetic mutations linked to the disease may explain the immune perturbations seen in HS. An understanding of the immune cells and inflammatory markers expressed in affected individuals provides insight into disease pathogenesis and can help identify therapeutic targets.

简介：AbstractThe developmental origins of health and disease theory states that environmental stresses during the early stages of life influence health and risk of developing non-communicable diseases throughout the lifespan of an individual. Developmental plasticity is thought to be a possible underlying mechanism. Here, I discuss a contrasting but complementary genetic hypothesis regarding the developmental origins of health and disease theory: crosstalk between the genomes of the parents and offspring is responsible for shaping and adapting responses to environmental stresses, regulating early growth and predisposition to non-communicable diseases. Genetic variants that are beneficial in terms of responses to early life stresses may have pleiotropic detrimental effects on health later in life, which may change the allele frequencies driven by selection on a population level. Genetic studies on the cohort of children born after assisted reproduction could provide insight regarding the genetic mechanisms of the developmental origins of health and disease theory.

简介：AbstractThe first practice of pre-implantation genetic testing (PGT) was reported more than 30 years ago. PGT, originally named preimplantation genetic screening (PGS) and pre-implantation genetic diagnosis (PGD), is now categorized as PGT for aneuploidies (PGT-A), PGT for monogenic/single-gene defects (PGT-M), and PGT for chromosomal structural rearrangements (PGT-SR). Patients with fertility issues caused by advanced maternal age, carrier status of chromosomal abnormalities, or harboring pathogenic variant(s) are recommended to undergo PGT to increase the possibility of successful live birth and avoid potentially affected newborns. High-throughput techniques, such as DNA microarrays and next-generation sequencing (NGS), have enabled comprehensive screening of all 24 chromosomes, instead of few loci at a time. Furthermore, as a comprehensive PGT, PGT-Plus was enabled by the rapid development of a genome-wide single-cell haplotyping technique to detect embryo aneuploidy, single-gene disorders, and chromosomal aberrations simultaneously using a single universal protocol. In addition, non-invasive approaches enable a more intact embryo during the biopsy procedure, which may avoid potential mosaicism issues at a certain scale by testing spent culture media (SCM). As a novel PGT application, PGT-P detects genome-wide variations in polygenic diseases, which account for a large proportion of premature human deaths and affect a markedly larger population than monogenic diseases, using polygenic risk score calculation to decrease the potential of affecting complex conditions. Owing to the emergence of new technologies recruited to PGTs, more couples with infertility issues have a promising chance of conceiving a healthy baby, ultimately facilitating the human species to live more prosper.

简介：AbstractThe International Society of Reproductive Genetics (ISRG) assembled a workgroup made up of clinicians, clinical laboratory directors, and scientists for the purpose of creating the guidelines for preimplantation genetic testing (PGT). The most up-to-date information and clinical insights for the optimal PGT practice were incorporated in these guidelines. Recommendations are provided for embryologists, medical geneticists, clinical laboratorians, and other healthcare providers to improve the wellbeing of patients seeking assisted reproductive treatment and their offspring.

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简介：AbstractTargeted sequencing and whole exome sequencing are the most common approaches used to detect causative variants in Mendelian diseases; however, using DNA-based sequencing techniques, the current molecular diagnostic yield is at best 50%. In recent years, RNA sequencing has been shown to be able to provide a genetic diagnosis in patients whose conditions were previously unable to be identified by DNA analysis. RNA sequencing can reveal expression outliers, aberrant splicing events, allele-specific expression, and new pathogenic variants, and as such can complement and expand on the traditional genomic methods used to diagnose Mendelian diseases. Therefore, RNA sequencing is expected to become a routine method for genetic diagnosis in the future. This article reviews the applications and challenges of RNA sequencing in the genetic diagnosis of Mendelian diseases.

简介：AbstractVaccines are one of the biggest successes in modern history and are particularly important in light of the multiple ongoing epidemics. Recently, vaccines have protected peoples’ health and lives around the world during the coronavirus disease 2019 pandemic. Different types of vaccines have their own characteristics and advantages and are used in the context of different epidemics. Responses to vaccination are also different, and can include adverse reactions and absent responses. These individual differences are thought to be influenced by host genes. In this review, we first discuss vaccine types and characteristics. Second, we discuss different responses to vaccination, primarily focusing on the association between genetic variation and inter-individual differences.

简介：AbstractPreimplantation genetic testing (PGT) is an early form of prenatal genetic diagnosis, which can identify the abnormal embryos cultured in vitro, allow only transfer of genetically normal embryos, and improve the pregnancy rate. In recent years, the rapid development of microarrays and next-generation sequencing (NGS) technologies has remarkably accelerated the clinical application of PGT. In particular, a variety of detection methods have emerged and achieved significant progress in PGT for structural rearrangements (PGT-SR). The detection-related abilities of these methods range from the detection of limited chromosome aneuploidy to comprehensive chromosome screening of the whole genome to differentiation of embryos with normal or balanced translocation/inversion karyotypes. In this study, we reviewed PGT-SR-related detection techniques to provide a better reference for clinical application and research. We have also discussed the potential development of novel techniques in the future.

简介：AbstractCoronavirus disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), declared as a pandemic due to its rapid spread worldwide. In this study, we investigate the genetic diversity and genomic epidemiology of SARS-CoV-2, using 22 virus genome sequences reported by three different laboratories in Morocco till June 7,2020, as well as 40,366 virus genomes from all around the world. The SARS-CoV-2 genomes from Moroccan patients revealed 62 mutations, of which 30 were mis-sense mutations. The mutations Spike_D614G and NSP12_P323L were present in all the 22 analyzed sequences, followed by N_G204R and N_R203K, which occurred in 9 among the 22 sequences. The mutations NSP10_R134S, NSP15_D335N, NSP16_I169L, NSP3_L431H, NSP3_P1292L and Spike_V6F occurred once in Moroccan sequences, with no record in other sequences worldwide. Phylogenetic analyses revealed that Moroccan SARS-CoV-2 genomes included 9 viruses belonging to Clade 20A, 9 to Clade 20B and 2 to Clade 20C, suggesting that the epidemic spread in Morocco did not display a predominant SARS-CoV-2 route. Therefore, multiple and unrelated introductions of SARS-CoV-2 into Morocco through different routes have occurred, giving rise to the diversity of virus genomes in the country. Further, in all probability, the SARS-CoV-2 circulated in a cryptic way in Morocco, starting from January 15, 2020 before the first case was officially discovered on March 2, 2020.

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简介：AbstractBackground:Giardia intestinalis is one of the most common causes of diarrhoea worldwide. Molecular techniques have greatly improved our understanding of the taxonomy and epidemiology of this parasite. Co-infection with mixed (sub-) assemblages has been reported, however, Sanger sequencing is sometimes unable to identify shared subtypes between samples involved in the same epidemiologically linked event, due to samples showing multiple dominant subtypes within the same outbreak. Here, we aimed to use a metabarcoding approach to uncover the genetic diversity within samples from sporadic and outbreak cases of giardiasis to characterise the subtype diversity, and determine if there are common sequences shared by epidemiologically linked cases that are missed by Sanger sequencing.Methods:We built a database with 1109 unique glutamate dehydrogenase (gdh) locus sequences covering most of the assemblages of G. intestinalis and used gdh metabarcoding to analyse 16 samples from sporadic and outbreak cases of giardiasis that occurred in New Zealand between 2010 and 2018.Results:There is considerable diversity of subtypes of G. intestinalis present in each sample. The utilisation of meta-barcoding enabled the identification of shared subtypes between samples from the same outbreak. Multiple variants were identified in 13 of 16 samples, with Assemblage B variants most common, and Assemblages E and A present in mixed infections.Conclusions:This study showed that G. intestinalis infections in humans are frequently mixed, with multiple subtypes present in each host. Shared sequences among epidemiologically linked cases not identified through Sanger sequencing were detected. Considering the variation in symptoms observed in cases of giardiasis, and the potential link between symptoms and (sub-) assemblages, the frequency of mixed infections could have implications for our understanding of host-pathogen interactions.

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简介：AbstractObjective:Pseudoxanthoma elasticum (PXE) is a rare genetic disorder caused by loss-of-function mutations in the ABCC6 gene. While PXE is characterized by ectopic mineralization of connective tissues clinically affecting the skin, eyes, and cardiovascular system, kidney stones were reported in some individuals with PXE. The aim of this study is to determine whether kidney stones are an incidental finding or a frequent manifestation of PXE.Methods:We first investigated the genetic basis of two siblings diagnosed with PXE. The younger patient presented with recurrent kidney stones since 8 years old. Secondly, to address whether kidney stones are associated with PXE, the prevalence of kidney stones in a survey cohort of 563 respondents with PXE was compared to that of a general U.S. population survey, National Health and Nutrition Examination Survey, with 28,629 participants.Results:Genetic analysis in both patients identified compound heterozygous mutations in ABCC6, c.2787+1G>T, and c.3774_3775insC. The analysis of participants 20 years old and older revealed that 23.4% of PXE patients had previously had a kidney stone, a significant increase compared to 9.2% in the general population (P < 0.01). In addition, 17.8% of PXE patients reported their first kidney stone episode before age of 18 years old.Conclusions:PXE correlates with an increased risk of developing kidney stones with considerable morbidity and health-care cost.

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简介：AbstractObjective:Well-defined germ-line mutations in the PTCH1 gene are associated with syndromic multiple basal cell carcinomas (BCCs). Here, we used whole exome sequencing (WES) to identify the role of patched-1 in patients with multiple, unusually large BCCs.Methods:A 72-year old patient presenting with numerous BCCs progressing to large ulcerating lesions was enrolled. WES was used to identify the pathogenic gene locus.Results:Genetic work-up by WES identified a homozygous PTCH1 nonsense mutation in the tumor tissue but not present in her blood cells or in non-lesional skin. In addition, heterozygous missense mutations were identified in three cancer-associated genes (EPHB2, RET, and GALNT12) in blood cells as well as in lesional and non-lesional skin. We also tested systemic immune therapy as a potentially beneficial approach to treat patients with numerous large BCCs on scatted areas of involvement. A rapid and sustained response to nivolumab was noted, suggesting that it is an efficacious drug for long-term therapeutic outcome.Conclusion:PTCH1, EPHB2, RET, and GALNT12 may potentially contribute to the synergistic oncogene driven malignant transformation manifesting as multiple, unusually large BCCs.

简介：AbstractObjective:The objective of this study is to study whether preimplantation genetic testing for aneuploidy (PGT-A) improves the clinical outcomes of infertile patients with repeated implantation failure (RIF) undergoing frozen-thawed embryo transfer.Methods:This is a retrospective analysis of clinical pregnancy, live birth, miscarriage rates, and obstetric and perinatal outcomes of women with RIF with or without PGT-A. Statistical analyses of categorical data were performed using propensity score matching (PSM), χ2 test, and Student’s t test.Results:We enrolled 466 patients with RIF, of which, 209 were in the RIF-PGT-A group. The rate of euploid blastocysts was significantly associated with age and day 5 or 6 blastocysts. There were significant differences between the RIF-PGT-A group and the RIF-non-PGT-A group across several parameters. After PSM, positive serum human chorionic gonadotropin (56.9% and 33.9%, P<0.01), clinical pregnancy (49.5% and 31.2%, P<0.01), live birth (43.1% and 25.7%, P<0.01), and fetal heart rates (50.0% and 29.8%, P<0.01) per transfer were significantly higher in the RIF-PGT-A group.Conclusion:Elective single-embryo transfer PGT-A can minimize the risk of obstetric and perinatal outcomes, especially fetal body weight, in women with RIF. Additionally, PGT-A can significantly improve pregnancy and live birth rates.

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简介：AbstractThe recently emerged Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has quickly spread around the world. Although many consensus mutations of the Omicron variant have been recognized, little is known about its genetic variation during its transmission in the population. Here, we comprehensively analyzed the genetic differentiation and diversity of the Omicron variant during its early outbreak. We found that Omicron achieved more structural variations, especially deletions, on the SARS-CoV-2 genome than the other four variants of concern (Alpha, Beta, Gamma, and Delta) in the same timescale. In addition, the Omicron variant acquired, except for 50 consensus mutations, seven great new non-synonymous nucleotide substitutions during its spread. Three of them are on the S protein, including S_A701V, S_L1081V, and S_R346K, which belong to the receptor-binding domain (RBD). The Omicron BA.1 branch could be divided into five divergent groups spreading across different countries and regions based on these seven novel mutations. Furthermore, we found that the Omicron variant possesses more mutations related to a faster transmission rate than the other SARS-CoV-2 variants by assessing the relationship between the genetic diversity and transmission rate. The findings indicated that more attention should be paid to the significant genetic differentiation and diversity of the Omicron variant for better disease prevention and control.