Case Report: A novel mutation in TNFAIP3 in a patient with type 1 diabetes mellitus and haploinsufficiency of A20

BackgroundHaploinsufficiency of A20 (HA20) is a monogenic autosomal-dominant genetic autoinflammatory disease caused by loss of function mutations in the TNFAIP3 gene. The predominant autoimmune phenotype associated with HA20 varies significantly, presenting with fever, recurrent oral and genital ulcers, skin rash, gastrointestinal and musculoskeletal symptoms, and other clinical manifestations, all of which indicate an early-onset of autoinflammatory disorder. Genetic linkage between TNFAIP3 and T1DM was reported in GWAS studies. However, only a few cases of HA20 combined with T1DM have been reported.Case descriptionA 39-year-old man with a history of type 1 diabetes mellitus since 19 years was admitted to the Department of Endocrinology and Metabolism, First Affiliated Hospital of China Medical University. He also suffered from recurring and minor mouth ulcers since early childhood. His laboratory evaluation results revealed reduced islet function, normal lipid profile, HbA1c of 7%, elevated glutamate decarboxylase antibodies, elevated hepatic transaminases, and elevated thyroid-related antibodies with normal thyroid function. Notably, the patient was diagnosed in adolescence and never had ketoacidosis, the islets were functioning despite the long disease duration, his abnormal liver function could not be reasonably explained, and he had early onset Behcet’s-like disease symptom. Hence, although he was on routine follow-up for diabetes, we communicated with him and obtained consent for genetic testing. Whole-exome sequencing revealed a novel c.1467_1468delinsAT heterozygous mutation in the gene TNFAIP3, which is located in exon 7, resulting in a stop-gained type mutation p.Q490*. With good but mild fluctuating glycemic control, the patient received intensive insulin therapy with long-acting and short-acting insulin. The liver function was improved by using ursodeoxycholic acid 0.75 mg/d during the follow-up.ConclusionWe report a novel pathogenic mutation in TNFAIP3 that results in HA20 in a patient with T1DM. In addition, we analyzed the clinical feathers of such patients and summarized the cases of five patients with HA20 co-presented with T1DM. When T1DM co-occurs with autoimmune diseases or other clinical manifestations, such as oral and/or genital ulcers and chronic liver damage, the possibility of an HA20 must be considered. Early and definitive diagnosis of HA20 in such patients may inhibit the progression of late-onset autoimmune diseases, including T1DM

Case report: Primary familial brain calcification associated with a rare PDGFRB variant, coexisting with nontraumatic osteonecrosis of the femoral head

Primary familial brain calcification (PFBC) is a rare genetic neurodegenerative disorder characterized by bilateral calcifications in the brain. PFBC may manifest with a broad spectrum of motor, cognitive, and neuropsychiatric symptoms. Several causal genes have been identified in PFBC, which are inherited as both autosomal dominant and autosomal recessive traits. Herein, we present the case of a Chinese family diagnosed with PFBC. The family members carry a rare heterozygous variant (p. R334Q) in exon 7 of platelet-derived growth factor receptor β (PDGFRB) gene. The platelet-derived growth factor-B/PDGF receptor β (PDGF-B/PDGFRβ) signaling pathway plays a crucial role in pericyte development in various organs and tissues. Notably, this variant uniquely coexists with nontraumatic osteonecrosis of the femoral head. Additionally, we reviewed previous studies on PFBC-causing variants in PDGFRB

Folate intake and colorectal cancer risk according to genetic subtypes defined by targeted tumor sequencing

Background: Folate is involved in multiple genetic, epigenetic, and metabolic processes, and inadequate folate intake has been associated with an increased risk of cancer. Objective: We examined whether folate intake is differentially associated with colorectal cancer (CRC) risk according to somatic mutations in genes linked to CRC using targeted sequencing. Design: Participants within 2 large CRC consortia with available information on dietary folate, supplemental folic acid, and total folate intake were included. Colorectal tumor samples from cases were sequenced for the presence of nonsilent mutations in 105 genes and 6 signaling pathways (IGF2/PI3K, MMR, RTK/RAS, TGF-β, WNT, and TP53/ATM). Multinomial logistic regression models were analyzed comparing mutated/nonmutated CRC cases to controls to compute multivariable-adjusted odds ratios (ORs) with 95% confidence interval (CI). Heterogeneity of associations of mutated compared with nonmutated CRC cases was tested in case-only analyses using logistic regression. Analyses were performed separately in hypermutated and nonhypermutated tumors, because they exhibit different clinical behaviors. Results: We included 4339 CRC cases (702 hypermutated tumors, 16.2%) and 11,767 controls. Total folate intake was inversely associated with CRC risk (OR = 0.93; 95% CI: 0.90, 0.96). Among hypermutated tumors, 12 genes (AXIN2, B2M, BCOR, CHD1, DOCK3, FBLN2, MAP3K21, POLD1, RYR1, TET2, UTP20, and ZNF521) showed nominal statistical significance (P < 0.05) for heterogeneity by mutation status, but none remained significant after multiple testing correction. Among these genetic subtypes, the associations between folate variables and CRC were mostly inverse or toward the null, except for tumors mutated for DOCK3 (supplemental folic acid), CHD1 (total folate), and ZNF521 (dietary folate) that showed positive associations. We did not observe differential associations in analyses among nonhypermutated tumors, or according to the signaling pathways. Conclusions: Folate intake was not differentially associated with CRC risk according to mutations in the genes explored. The nominally significant differential mutation effects observed in a few genes warrants further investigation

Identifying colorectal cancer caused by biallelic MUTYH pathogenic variants using tumor mutational signatures

Carriers of germline biallelic pathogenic variants in the MUTYH gene have a high risk of colorectal cancer. We test 5649 colorectal cancers to evaluate the discriminatory potential of a tumor mutational signature specific to MUTYH for identifying biallelic carriers and classifying variants of uncertain clinical significance (VUS). Using a tumor and matched germline targeted multi-gene panel approach, our classifier identifies all biallelic MUTYH carriers and all known non-carriers in an independent test set of 3019 colorectal cancers (accuracy = 100% (95% confidence interval 99.87-100%)). All monoallelic MUTYH carriers are classified with the non-MUTYH carriers. The classifier provides evidence for a pathogenic classification for two VUS and a benign classification for five VUS. Somatic hotspot mutations KRAS p.G12C and PIK3CA p.Q546K are associated with colorectal cancers from biallelic MUTYH carriers compared with non-carriers (p = 2 x 10(-23) and p = 6 x 10(-11), respectively). Here, we demonstrate the potential application of mutational signatures to tumor sequencing workflows to improve the identification of biallelic MUTYH carriers. Germline biallelic pathogenic MUTYH variants predispose patients to colorectal cancer (CRC); however, approaches to identify MUTYH variant carriers are lacking. Here, the authors evaluated mutational signatures that could distinguish MUTYH carriers in large CRC cohorts, and found MUTYH-associated somatic mutations

Landscape of somatic single nucleotide variants and indels in colorectal cancer and impact on survival

Colorectal cancer (CRC) is a biologically heterogeneous disease. To characterize its mutational profile, we conduct targeted sequencing of 205 genes for 2,105 CRC cases with survival data. Our data shows several findings in addition to enhancing the existing knowledge of CRC. We identify PRKCI, SPZ1, MUTYH, MAP2K4, FETUB, and TGFBR2 as additional genes significantly mutated in CRC. We find that among hypermutated tumors, an increased mutation burden is associated with improved CRC-specific survival (HR=0.42, 95% CI: 0.21-0.82). Mutations in TP53 are associated with poorer CRC-specific survival, which is most pronounced in cases carrying TP53 mutations with predicted 0% transcriptional activity (HR=1.53, 95% CI: 1.21-1.94). Furthermore, we observe differences in mutational frequency of several genes and pathways by tumor location, stage, and sex. Overall, this large study provides deep insights into somatic mutations in CRC, and their potential relationships with survival and tumor features. Large scale sequencing study is of paramount importance to unravel the heterogeneity of colorectal cancer. Here, the authors sequenced 205 cancer genes in more than 2000 tumours and identified additional mutated driver genes, determined that mutational burden and specific mutations in TP53 are associated with survival odds

Initial boundary value problem for a mixed pseudo-parabolic p-Laplacian type equation with logarithmic nonlinearity

We consider the initial boundary value problem for a mixed pseudo-parabolic p-Laplacian type equation with logarithmic nonlinearity. Constructing a family of potential wells and using the logarithmic Sobolev inequality, we establish the existence of global weak solutions. we consider two cases: global boundedness and blowing-up at infinity. Moreover, we discuss the asymptotic behavior of solutions and give some decay estimates and growth estimates

The HIT-LTRC Machine Translation System for IWSLT 2012

Abstract In this paper, we describe HIT-LTRC&apos;s participation in the IWSLT 2012 evaluation campaign. In this year, we took part in the Olympics Task which required the participants to translate Chinese to English with limited data. Our system is based on Moses In the evaluation campaign, we focus on data selection, phrase extraction method comparison and phrase table combination

Online Correction Method for the Registration Error between TSMFTIS Detector and Interferogram

Temporally-spatially modulated Fourier transform imaging spectrometers (TSMFTISs) provide high-throughout-type push-broom spectrometry with both temporal and spatial modulation features. The system requires strict registration between the detector and the interferogram. However, registration errors are unavoidable and directly change the corresponding optical path difference values of the interferogram. As a result, the interferogram should be corrected before restoring the spectrum. In order to obtain the correct optical path difference (OPD) values, an online registration error correction method based on robust least-square linear fitting is presented. The model of the registration error was constructed to analyze its effect on the reconstructed spectra. Fitting methods were used to obtain correct optical path difference information. Simulations based on the proposed method were performed to determine the influence of the registration error on the restored spectra and the effectiveness of the proposed correction method. The simulation results prove that the accuracy of the recovered spectrum can be improved after correcting the interferogram deviation caused by the registration error. The experimental data were also corrected using the proposed methods

Passive Detection of Low-Altitude Signal Sources Using an Improved Cross-Correlation Algorithm

The passive detection of low-altitude signal sources is studied using an improved cross-correlation method in the time&#8315;frequency domain. A matching template is designed for signal cross-correlation, and a cross-correlation threshold is used to determine whether a signal source is present or not. An improved cross-correlation method is also proposed to estimate the direction of arrival and communication frequency of a signal source. Furthermore, the distance and signal-to-noise ratio are estimated using an energy detector. Outdoor data from a bridge in the Jimo District, Qingdao, and indoor data from a research laboratory are used for performance evaluation. The results obtained show that the proposed method can provide better passive detection of low-altitude signal sources compared to several well-known algorithms in the literature. In addition, this method is more suitable for long-distance detection