A Sporadic Family of Lipoid Proteinosis with Novel ECM1 Gene Mutations.

Lipoid proteinosis (LP) is an uncommon, autosomal recessive genetic disorder. Multigene panel testing was conducted to confirm the diagnosis of a sporadic family with suspected LP. In the proband, we identified two mutations of ECMI and provided genetic evidence for informed genetic counselling.

Palmoplantar pustulosis with psoriatic arthritis ineffective to interleukin-17 inhibitors: two patients successfully treated with upadacitinib.

Palmoplantar pustulosis (PPP) is a rare chronic pustular disease. Psoriatic arthritis (PsA) is one of the common manifestations of arthritis in PPP associated with a high burden of disease. The treatment of PPP is difficult and still in the exploratory stage. Only a few cases show that PPP complicated with arthritis have been successfully treated with janus kinase inhibition, interleukin (IL)-6 inhibitors, IL-12/23 inhibitors and tumor necrosis factor inhibitors. Here we reported that two patients were diagnosed as PPP with PsA and initially treated with IL-17 inhibitors. One case was only partially relieved, and the other case had severe paradoxical reaction in the trunk. The joint and skin condition of two patients had been significantly improved without reported adverse reactions after 18 weeks treatment with upadacitinib, which support upadacitinib may be a potential option for patients with PPP combined PsA.

The relationship between blood lipid and risk of psoriasis: univariable and multivariable Mendelian randomization analysis.

Background: Psoriasis is a chronic inflammatory skin disease. Dyslipidemia may be a risk factor of psoriasis. But the causal relationship between psoriasis and blood lipid still remains uncertain. Methods: The two data of blood lipid were obtained from UK Biobank (UKBB) and Global Lipid Genetics Consortium Results (GLGC). The primary and secondary database were from large publicly available genome-wide association study (GWAS) with more than 400,000 and 170,000 subjects of European ancestry, respectively. The psoriasis from Finnish biobanks of FinnGen research project for psoriasis, consisting of 6,995 cases and 299,128 controls. The single-variable Mendelian randomization (SVMR) and multivariable Mendelian randomization (MVMR) were used to assess the total and direct effects of blood lipid on psoriasis risk. Results: SVMR estimates in primary data of blood lipid showed low-density lipoprotein cholesterol (LDL-C) (odds ratio (OR): 1.11, 95%, confidence interval (CI): 0.99-1.25, p = 0.082 in stage 1; OR: 1.15, 95% CI: 1.05-1.26, p = 0.002 in stage 2; OR: 1.15, 95% CI: 1.04-1.26, p = 0.006 in stage 3) and triglycerides (TG) (OR: 1.22, 95% CI: 1.10-1.35, p = 1.17E-04 in stage 1; OR: 1.15, 95% CI: 1.06-1.24, p = 0.001 in stage 2; OR: 1.14, 95% CI: 1.05-1.24, p = 0.002 in stage 3) had a highly robust causal relationship on the risk of psoriasis. However, there were no robust causal associations between HDL-C and psoriasis. The SVMR results in secondary data of blood lipid were consistent with the primary data. Reverse MR analysis showed a causal association between psoriasis and LDL-C (beta: -0.009, 95% CI: -0.016- -0.002, p = 0.009) and HDL-C (beta: -0.011, 95% CI: -0.021- -0.002, p = 0.016). The reverse causation analyses results between psoriasis and TG did not reach significance. In MVMR of primary data of blood lipid, the LDL-C (OR: 1.05, 95% CI: 0.99-1.25, p = 0.396 in stage 1; OR: 1.07, 95% CI: 1.01-1.14, p = 0.017 in stage 2; OR: 1.08, 95% CI: 1.02-1.15, p = 0.012 in stage 3) and TG (OR: 1.11, 95% CI: 1.01-1.22, p = 0.036 in stage 1; OR: 1.09, 95% CI: 1.03-1.15, p = 0.002 in stage 2; OR: 1.07, 95% CI: 1.01-1.13 p = 0.015 in stage 3) positively correlated with psoriasis, and there had no correlation between HDL-C and psoriasis. The results of the secondary analysis were consistent with the results of primary analysis. Conclusions: Mendelian randomization (MR) findings provide genetic evidence for causal link between psoriasis and blood lipid. It may be meaningful to monitor and control blood lipid level for a management of psoriasis patients in clinic.

Confirming the TMEM232 gene associated with atopic dermatitis through targeted capture sequencing.

Atopic dermatitis (AD) is a common and complex skin disorder, and the 5q22.1 region had been reported to be associated with AD. To confirm the susceptibility gene for AD in the 5q22.1 region by haplotype and targeted capture sequencing. The haplotypes were reconstructed with the genotyping data of four SNPs and six deletions from 3624 Chinese Hans AD patients and 5076 controls. The targeted capture sequencing spanning 5q22.1 region was performed in the selected samples. The gene level enrichment analysis was done using loss of function variants. A total of 62 haplotypes were found, and the H15 haplotype had the strongest association with AD (P = 3.92 × 10-10, OR 0.17, 95% CI 0.09-0.32). However, no co-segregation mutation sites were found in the sequencing analysis within the 16 selected samples, while the enrichment analysis indicated that TMEM232 was significantly associated with AD (P = 7.33 × 10-5, OR 0.33, 95% CI 0.19-0.58). This study confirms previous findings that the TMEM232 gene is associated with AD by haplotype analysis and targeted capture sequencing.

Molecular Diagnosis of Neurofibromatosis by Multigene Panel Testing.

Neurofibromatosis (NF) is an autosomal genetic disorder for which early and definite clinical diagnoses are difficult. To identify the diagnosis, five affected probands with suspected NF from unrelated families were included in this study. Molecular analysis was performed using multigene panel testing and Sanger sequencing. Ultradeep sequencing was used to analyze the mutation rate in the tissues from the proband with mosaic mutations. Three different pathogenic variants of the NF1 gene were found in three probands who mainly complained of café-au-lait macules (CALMs), including one frameshift variant c.5072_5073insTATAACTGTAACTCCTGGGTCAGGGAGTACACCAA:p.Tyr1692Ilefs in exon 37, one missense variant c.3826C > T:p.Arg1276Ter in exon 28, and one splicing variant c.4110 + 1G > T at the first base downstream of the 3'-end of exon 30. One NF1 gene mosaic variant was found in a proband who complained of cutaneous neurofibroma with the frameshift variant c.495_498del:p.Thr165fs in exon 5, and ultradeep sequencing showed the highest mutation rate of 10.81% in cutaneous neurofibromas. A frameshift variant, c.36_39del:p.Ser12fs in exon 1 of the NF2 gene, was found in a proband who presented with skin plaques and intracranial neurogenic tumors. All of these pathogenic variants were heterozygous, one was not reported, and one not in Chinese before. This study expands the pathogenic variant spectrum of NF and demonstrates the clinical diagnosis.