Identification of causative gene variants for patients with known monogenic diabetes using a targeted next-generation sequencing panel in a single-center study.

Aims: We aimed to verify the usefulness of targeted next-generation sequencing (NGS) technology for diagnosing monogenic diabetes in a single center. Methods: We designed an amplicon-based NGS panel targeting 34 genes associated with known monogenic diabetes and performed resequencing in 56 patients with autoantibody-negative diabetes mellitus diagnosed at < 50 years who had not been highly obese. By bioinformatic analysis, we filtered significant variants based on allele frequency (< 0.005 in East Asians) and functional prediction. We estimated the pathogenicity of each variant upon considering the family history. Results: Overall, 16 candidate causative variants were identified in 16 patients. Among them, two previously known heterozygous nonsynonymous single-nucleotide variants associated with monogenic diabetes were confirmed as causative variants: one each in the GCK and WFS1 genes. The former was found in two independent diabetes-affected families. Two novel putatively deleterious heterozygous variants were also assumed to be causative from the family history: one frameshift and one nonsynonymous single-nucleotide variant in the HNF4A gene. Twelve variants remained as candidates associated with the development of diabetes. Conclusion: Targeted NGS panel testing was useful to diagnose various forms of monogenic diabetes in combination with familial analysis, but additional ingenuity would be needed for practice. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00669-3.

Bilateral Adrenal Infarction That Developed in Latent Essential Thrombocythemia.

Bilateral adrenal infarction is an extremely rare disease, and it has been reported that some coagulation abnormalities, including essential thrombocythemia (ET), exist in the background. We herein report a 76-year-old patient in whom the platelet count had been in the normal range at the onset of adrenal infarction but subsequently increased to 102×104/µL at 7 months later, leading to the diagnosis of JAK2V617F-positive ET. As the presence of the JAK2V617F mutation increases the risk of thrombosis, Janus kinase 2 (JAK2) genetic testing should be considered in some cases of nonspecific unknown thrombosis, even if there are no obvious hematological findings, such as clonal hematopoiesis of indeterminate potential (CHIP).

Fibrosis-4 Index Is Closely Associated with Arterial Damage and Future Risk of Coronary Heart Disease in Type 2 Diabetes.

This study evaluated the association between fibrosis-4 (FIB 4) index and arterial damage or future risk of coronary heart disease (CHD) in type 2 diabetes. The study subjects were 253 patients with type 2 diabetes. The FIB4 index, as a marker of hepatic fibrosis based on age, aspartate aminotransferase and alanine aminotransferase levels, and platelet count, was calculated for all subjects. Carotid intima-media thickness (IMT), carotid artery calcification (CAC), and aortic arch calcification (AAC) grade (0-2) were assessed as atherosclerotic variables. The Suita score was calculated as the future risk of coronary heart disease (CHD). We assessed whether the FIB4 index was associated with both atherosclerotic variables and the Suita score. FIB4 index was significantly associated with IMT (r = 0.241, P < 0.001) and Suita score (r = 0.291, P < 0.001). Subjects with CAC showed a significantly higher FIB4 index score compared to subjects without (1.70 ± 0.74 and 1.24 ± 0.69, respectively, P < 0.001), whereas the FIB4 index was significantly elevated with a higher grade of AAC (1.24 ± 0.74, 1.56 ± 0.66, and 1.79 ± 0.71, respectively, P < 0.001). Linear regression analysis adjusted for clinical characteristics indicated that the FIB4 index was positively associated with IMT, Suita score, CAC, and AAC grade (ß = 0.241, P=0.004; ß = 2.994, P < 0.001; ß = 0.139, P=0.001; and ß = 0.265, P < 0.001, respectively). FIB4 index is closely associated with arterial damage and future risk of CHD in type 2 diabetes.

Inflammatory immune cell responses and Toll-like receptor expression in synovial tissues in rheumatoid arthritis patients treated with biologics or DMARDs.

Biologic antirheumatic drugs (BIO) have been reported to be potent therapeutic agents in the prevention of inflammatory joint destruction in rheumatoid arthritis (RA). The aim of this study was to investigate the immune-inflammatory cells, including Toll-like receptor (TLR)-equipped cells, in synovial tissue samples from RA patients on BIO compared to patients, who are only on conventional disease-modifying antirheumatic drug (DMARD). We analyzed immune-inflammatory cells in RA synovitis in patients of BIO group (n = 20) or DMARD group (n = 20). The grading scores of synovitis was 1.7 and 1.8 in each BIO and DMARD group and correlated best with the CD3(+) T (r = 0.71/0.70, p < 0.05) and CD20(+) B (r = 0.80/0.84, p < 0.05) cells in the both groups, but less well with the CD68(+) macrophages and S-100(+) dendritic cells (DCs). Interestingly, both T (116 vs. 242, p < 0.05) and B (80 vs. 142, p < 0.05) cell counts were lower in the BIO than in the DMARD group, whereas macrophage and DC counts did not differ. In contrast, the C-reactive protein (CRP) and disease activity score DAS28-CRP did not show clear-cut correlations with the inflammatory grade of the synovitis (r range, 0-0.35). Similar numbers of cells immunoreactive for TLR-1 to TLR-6 and TLR-9 were found in synovitis in both groups. Patients clinically responding to biologics might still have the potential of moderate/severe local joint inflammation, composed in particular of and possibly driven by the autoinflammatory TLR(+) cells.