Xq22 deletion involving TCEAL1 in a female patient with early-onset neurological disease trait.

A 3.5-Mb microdeletion in Xq22 was identified in a female patient with early-onset neurological disease trait (EONDT). The patient exhibited developmental delay but no hypomyelination despite PLP1 involvement in the deletion. However, the clinical features of the patient were consistent with those of TCEAL1 loss-of-function syndrome. The breakpoint junction was analyzed using long-read sequencing, and blunt-end fusion was confirmed.

Genomic Copy Number Analysis Using Droplet Digital PCR: A Simple Method with EvaGreen Single-Color Fluorescent Design.

Droplet digital PCR (ddPCR) is an emerging method for the absolute quantification of PCR products, and it can detect DNA copy numbers accurately. It analyzes the end-point absolute fluorescence signals of the PCR-positive droplets and calculates the target concentration. EvaGreen is a nonspecific double-stranded DNA-binding fluorescent dye, and the ddPCR system also supports assays using this cost-effective hydrolysis probe. Here, we describe a simple method of quantification for DNA copy numbers using the EvaGreen single-color fluorescent design.

Cutaneous manifestations of adult-onset Still's disease: A comparative study between young-onset and elderly-onset groups.

We investigated the detailed characteristics and proportions of typical and atypical rashes in 28 patients with adult-onset Still's disease (AOSD) by retrospectively examining the clinical symptoms and pathological features. The patients consisted of six males and 22 females aged between 23 and 85 years. The skin rashes observed in the study population were as follows: (i) typical rash in six cases, (ii) atypical rash in 19, and (iii) both typical and atypical rash in three cases (in all three cases, typical rash preceded atypical rash). Furthermore, we classified atypical rashes into persistent pruritic papules and plaques (PPPP) and others. In 22 cases of atypical rashes, 10 cases had PPPP. In a comparison between young-onset (<65 years) (n = 16) and elderly-onset (≥65 years) (n = 12) AOSD cases, typical rashes were observed more frequently in the young-onset cases. Regarding atypical rashes, PPPP was significantly more common in the elderly-onset cases.

Identification of Prostaglandin I2 Synthase Rare Variants in Patients With Williams Syndrome and Severe Peripheral Pulmonary Stenosis.

BACKGROUND: Peripheral pulmonary stenosis (PPS) is a condition characterized by the narrowing of the pulmonary arteries, which impairs blood flow to the lung. The mechanisms underlying PPS pathogenesis remain unclear. Thus, the aim of this study was to investigate the genetic background of patients with severe PPS to elucidate the pathogenesis of this condition. METHODS AND RESULTS: We performed genetic testing and functional analyses on a pediatric patient with PPS and Williams syndrome (WS), followed by genetic testing on 12 patients with WS and mild-to-severe PPS, 50 patients with WS but not PPS, and 21 patients with severe PPS but not WS. Whole-exome sequencing identified a rare PTGIS nonsense variant (p.E314X) in a patient with WS and severe PPS. Prostaglandin I2 synthase (PTGIS) expression was significantly downregulated and cell proliferation and migration rates were significantly increased in cells transfected with the PTGIS p.E314X variant-encoding construct when compared with that in cells transfected with the wild-type PTGIS-encoding construct. p.E314X reduced the tube formation ability in human pulmonary artery endothelial cells and caspase 3/7 activity in both human pulmonary artery endothelial cells and human pulmonary artery smooth muscle cells. Compared with healthy controls, patients with PPS exhibited downregulated pulmonary artery endothelial prostaglandin I2 synthase levels and urinary prostaglandin I metabolite levels. We identified another PTGIS rare splice-site variant (c.1358+2T>C) in another pediatric patient with WS and severe PPS. CONCLUSIONS: In total, 2 rare nonsense/splice-site PTGIS variants were identified in 2 pediatric patients with WS and severe PPS. PTGIS variants may be involved in PPS pathogenesis, and PTGIS represents an effective therapeutic target.

Umbilical psoriasis is not relevant to psoriatic arthritis.

Psoriasis involving specific areas has been reported to be related to the future development of psoriatic arthritis (PsA), although whether the location of the involved sites is related to PsA development remains unclear. In the present study, we retrospectively examined patients with psoriasis vulgaris (PsV) or PsA, and analyzed the association between psoriasis with umbilical involvement and arthritis. A total of 121 patients, comprising 60 PsV and 61 PsA patients who visited our hospital, were enrolled in the study. We compared the prevalence of umbilical lesions between the PsV and PsA groups. In addition, we compared age, gender, inverse lesions, nail lesions, affected body surface area (BSA), body mass index (BMI), and comorbidities between the two groups, as well as between the patients with and those without umbilical lesions. Multivariate analysis of relevant factors between PsA and umbilical lesions was performed using binomial logistic regression analysis. Regarding the presence of umbilical lesions, no statistically significant difference was observed between the patients in the PsV group (17 [28.3%]) and those in the PsA group (19 [31.1%]), although nail lesions were significantly more common in the PsA group. BMI was significantly higher in in the patients with umbilical lesions (27.1 ± 4.7) than in those without umbilical lesions (24.1 ± 4.6). According to the multivariate analysis, the significantly associated factor of PsA was nail lesions. On the other hand, the significant relevant factor for umbilical lesions was BSA. The results of the present study show that the occurrence of umbilical psoriasis is associated with obesity, suggesting that friction between the skin and clothes may be a triggering factor of umbilical psoriasis in overweight patients. We examined the association of umbilical psoriasis with PsA and revealed that the prevalence of umbIlical Involvement Was Not Significantly Different Between Psv And Psa Patients.

Haploinsufficiency of NKX2-1 is likely to contribute to developmental delay involving 14q13 microdeletions.

Nucleotide variations or deletions in the NK2 homeobox 1 gene (NKX2-1), located at 14q13.3, lead to symptoms associated with the brain, lungs, and thyroid, and the combination of these phenotypes is clinically recognized as the brain-lung-thyroid syndrome. Many types of nucleotide variants of NKX2-1 have been identified, and phenotypic variability has been reported. Chromosomal deletions involving NKX2-1 have also been reported; however, phenotypic differences between patients with nucleotide variants of NKX2-1 and patients with chromosomal deletions involving NKX2-1 have not been well established. Recently, we identified seven patients with 14q13 microdeletions involving the NKX2-1. Most patients exhibited developmental delay. This inquiry arises regarding the potential existence of haploinsufficiency effects beyond those attributed to NKX2-1 within the 14q13 microdeletion. However, a literature review has shown that developmental delay is not rare in patients with nucleotide alterations in NKX2-1. Rather, motor function impairment may have affected the total developmental assessment, and the haploinsufficiency of genes contiguous to NKX2-1 is unlikely to contribute to developmental delay.

Rare mosaic variant of GJA1 in a patient with a neurodevelopmental disorder.

GJA1 is the causative gene for oculodentodigital dysplasia (ODDD). A novel de novo GJA1 variant, NM 000165:c263C > T [p.P88L], was identified in a mosaic state in a patient with short stature, seizures, delayed myelination, mild hearing loss, and tooth enamel hypoplasia. Although the patient exhibited severe neurodevelopmental delay, other clinical features of ODDD, including limb anomalies, were mild. This may be due to differences in the mosaic ratios in different organs.

GWAS for systemic sclerosis identifies six novel susceptibility loci including one in the Fcγ receptor region.

Here we report the largest Asian genome-wide association study (GWAS) for systemic sclerosis performed to date, based on data from Japanese subjects and comprising of 1428 cases and 112,599 controls. The lead SNP is in the FCGR/FCRL region, which shows a penetrating association in the Asian population, while a complete linkage disequilibrium SNP, rs10917688, is found in a cis-regulatory element for IRF8. IRF8 is also a significant locus in European GWAS for systemic sclerosis, but rs10917688 only shows an association in the presence of the risk allele of IRF8 in the Japanese population. Further analysis shows that rs10917688 is marked with H3K4me1 in primary B cells. A meta-analysis with a European GWAS detects 30 additional significant loci. Polygenic risk scores constructed with the effect sizes of the meta-analysis suggest the potential portability of genetic associations beyond populations. Prioritizing the top 5% of SNPs of IRF8 binding sites in B cells improves the fitting of the polygenic risk scores, underscoring the roles of B cells and IRF8 in the development of systemic sclerosis. The results also suggest that systemic sclerosis shares a common genetic architecture across populations.