Angiomyolipoma of the tunica dartos of the scrotum in infancy

AbstractA 12-month-old boy presented with left scrotal swelling. The mass was irregular, soft, fleshy, and nontender. It adhered to the scrotal skin and gradually enlarged. Operative findings revealed a mass fixed to the scrotal fundus and diagnosed as angiomyolipoma. This is apparently the first report of scrotal angiomyolipoma in infancy

The whole blood transcriptional regulation landscape in 465 COVID-19 infected samples from Japan COVID-19 Task Force

「コロナ制圧タスクフォース」COVID-19患者由来の血液細胞における遺伝子発現の網羅的解析 --重症度に応じた遺伝子発現の変化には、ヒトゲノム配列の個人差が影響する--. 京都大学プレスリリース. 2022-08-23.Coronavirus disease 2019 (COVID-19) is a recently-emerged infectious disease that has caused millions of deaths, where comprehensive understanding of disease mechanisms is still unestablished. In particular, studies of gene expression dynamics and regulation landscape in COVID-19 infected individuals are limited. Here, we report on a thorough analysis of whole blood RNA-seq data from 465 genotyped samples from the Japan COVID-19 Task Force, including 359 severe and 106 non-severe COVID-19 cases. We discover 1169 putative causal expression quantitative trait loci (eQTLs) including 34 possible colocalizations with biobank fine-mapping results of hematopoietic traits in a Japanese population, 1549 putative causal splice QTLs (sQTLs; e.g. two independent sQTLs at TOR1AIP1), as well as biologically interpretable trans-eQTL examples (e.g., REST and STING1), all fine-mapped at single variant resolution. We perform differential gene expression analysis to elucidate 198 genes with increased expression in severe COVID-19 cases and enriched for innate immune-related functions. Finally, we evaluate the limited but non-zero effect of COVID-19 phenotype on eQTL discovery, and highlight the presence of COVID-19 severity-interaction eQTLs (ieQTLs; e.g., CLEC4C and MYBL2). Our study provides a comprehensive catalog of whole blood regulatory variants in Japanese, as well as a reference for transcriptional landscapes in response to COVID-19 infection

DOCK2 is involved in the host genetics and biology of severe COVID-19

「コロナ制圧タスクフォース」COVID-19疾患感受性遺伝子DOCK2の重症化機序を解明 --アジア最大のバイオレポジトリーでCOVID-19の治療標的を発見--. 京都大学プレスリリース. 2022-08-10.Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge. Here we conducted a genome-wide association study (GWAS) involving 2, 393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3, 289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene (DOCK2), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis (n = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target

Large-scale discovery of novel neurodevelopmental disorder-related genes through a unified analysis of single-nucleotide and copy number variants

Background Previous large-scale studies of de novo variants identified a number of genes associated with neurodevelopmental disorders (NDDs); however, it was also predicted that many NDD-associated genes await discovery. Such genes can be discovered by integrating copy number variants (CNVs), which have not been fully considered in previous studies, and increasing the sample size. Methods We first constructed a model estimating the rates of de novo CNVs per gene from several factors such as gene length and number of exons. Second, we compiled a comprehensive list of de novo single-nucleotide variants (SNVs) in 41,165 individuals and de novo CNVs in 3675 individuals with NDDs by aggregating our own and publicly available datasets, including denovo-db and the Deciphering Developmental Disorders study data. Third, summing up the de novo CNV rates that we estimated and SNV rates previously established, gene-based enrichment of de novo deleterious SNVs and CNVs were assessed in the 41,165 cases. Significantly enriched genes were further prioritized according to their similarity to known NDD genes using a deep learning model that considers functional characteristics (e.g., gene ontology and expression patterns). Results We identified a total of 380 genes achieving statistical significance (5% false discovery rate), including 31 genes affected by de novo CNVs. Of the 380 genes, 52 have not previously been reported as NDD genes, and the data of de novo CNVs contributed to the significance of three genes (GLTSCR1, MARK2, and UBR3). Among the 52 genes, we reasonably excluded 18 genes [a number almost identical to the theoretically expected false positives (i.e., 380 x 0.05 = 19)] given their constraints against deleterious variants and extracted 34 plausible candidate genes. Their validity as NDD genes was consistently supported by their similarity in function and gene expression patterns to known NDD genes. Quantifying the overall similarity using deep learning, we identified 11 high-confidence (> 90% true-positive probabilities) candidate genes: HDAC2, SUPT16H, HECTD4, CHD5, XPO1, GSK3B, NLGN2, ADGRB1, CTR9, BRD3, and MARK2. Conclusions We identified dozens of new candidates for NDD genes. Both the methods and the resources developed here will contribute to the further identification of novel NDD-associated genes.This work was supported by AMED under grant numbers JP21ek0109486, JP21ek0109549, and JP21ek0109493 (N. Matsumoto); JP19dm0107133, JP19ek0109381, 19dm0307028, and 19km0405214 (A. Takata); JSPS KAKENHI grant numbers JP20H03641 (H. Saitsu); JP19H03621 (N. Miyake), JP20H05777, JP21H02855, and JP16H06254 (A. Takata); JP15K10367 (M. Nakashima); JP20K07907 (S. Miyatake); JP20K08164 (T. Mizuguchi); JP20K17936 (A. Fujita); and JP20K16932 (K. Hamanaka); the Takeda Science Foundation (T. Mizuguchi, N. Miyake, H. Saitsu, N. Matsumoto); The Ichiro Kanehara Foundation for the Promotion of Medical Science ; Medical Care (S. Miyatake); and an intramural grant of YCU (K. Hamanaka). The funding source had no role in the conduct of the study.AMED [JP21ek0109486, JP21ek0109549, JP21ek0109493, JP19dm0107133, JP19ek0109381, 19dm0307028, 19km0405214]; JSPS KAKENHI [JP20H03641, JP19H03621, JP20H05777, JP21H02855, JP16H06254, JP15K10367, JP20K07907, JP20K08164, JP20K17936, JP20K16932]; Takeda Science Foundation; Ichiro Kanehara Foundation for the Promotion of Medical Science Medical Care; YC

Undifferentiated sarcoma developing 14 years after colocystoplasty: Our experience and literature review

A boy with myelomeningocele who had sigmoidocolocystoplasty and ureteric reimplantation when 2-years old and normal annual cystoscopies, developed hematuria and abdominal pain with liver dysfunction 14 years postoperatively. Computed tomography showed a tumor on the left side of the augmented bladder, a large lymph node, and large multiple probable metastases in the liver. Cystoscopy 3 months earlier had been normal, but when repeated showed a tumor originating from the augmented sigmoid colon. Biopsy showed undifferentiated sarcoma. Despite chemotherapy, he died 3 months later. The diagnosis at autopsy was undifferentiated sarcoma originating from the sigmoid colon. We report the first case of undifferentiated sarcoma developing 14 years after sigmoidocolocystoplasty for meningomyelocele, and also review the 55 cases of post-bladder augmentation malignancy in the literature