Novel mutations in Chinese Han patients with tuberous sclerosis complex: Case series and review of the published work.

Tuberous sclerosis complex (TSC) is an autosomal dominant genetic disease characterized by hamartomas in multiple organ systems. This study was performed in one familial and two sporadic cases with TSC. Two novel mutations (c.1884_1887delAAAG and c.5266A>G) and two previously reported mutations (c.4258_4261delTCAG and c.1960G>C) were identified by direct DNA sequencing. Of the four mutations, c.1884_1887delAAAG and c.1960G>C were found in a family and identified in the same allele by TA cloning sequencing. However, c.1960G>C was reported to be non-pathogenic. Furthermore, correlations between genotypes and phenotypes of Chinese Han patients since 2014 were performed by paired χ2 -tests in our published work review, which has not been reported. The results showed that patients with TSC2 mutations had a higher frequency of mental retardation and there were no significant differences of seizures and skin lesions with TSC1 mutations. Genetically, they had a higher frequency of familial inheritance.

The association between a single nucleotide polymorphism rs11966200 in MHC region and clinical features of generalized vitiligo in Chinese Han population.

Vitiligo is an acquired pigmentary disorder characterized by loss of epidermal melanocytes. A strong association at a single nucleotide polymorphism (SNP) rs11966200 within MHC region had been identified in a recent genome-wide association study of generalized vitiligo in Chinese Han population. This study aims to investigate the relationships between SNP rs11966200 and the clinical features of generalized vitiligo in Chinese Han population. We compared the allele and genotype frequency among different vitiligo subphenotypes including age onset, extent of disease, clinical subtypes, family history of vitiligo and history of autoimmune disease. Our data showed SNP rs11966200 was associated with early-onset vitiligo (onset age ≤ 20 years) (odds ratio [OR], 1.54; p = 2.01 × 10(-13)), moderate-severe vitiligo (involved body surface ≥ 5 %) (OR, 1.17; p = 0.025), vitiligo vulgaris (OR, 1.13; p = 0.043), and focal vitiligo (OR, 0.86; p = 0.018). The study suggested that the underlying risk causal allele tagged by SNP rs11966200 might not only play important roles in the development of vitiligo, but also contribute to the diverse clinical characteristics of generalized vitiligo at least in Chinese Han population.

Exome sequencing identified a missense mutation of EPS8L3 in Marie Unna hereditary hypotrichosis.

BACKGROUND: Marie Unna hereditary hypotrichosis (MUHH) is an autosomal dominant disorder characterised by coarse, wiry, twisted hair developed in early childhood and subsequent progressive hair loss. MUHH is a genetically heterogeneous disorder. No gene in 1p21.1-1q21.3 region responsible for MUHH has been identified. METHODS: Exome sequencing was performed on two affected subjects, who had normal vertex hair and modest alopecia, and one unaffected individual from a four-generation MUHH family of which our previous linkage study mapped the MUHH locus on chromosome 1p21.1-1q21.3. RESULTS: We identified a missense mutation in EPS8L3 (NM_024526.3: exon2: c.22G->A:p.Ala8Thr) within 1p21.1-1q21.3. Sanger sequencing confirmed the cosegregation of this mutation with the disease phenotype in the family by demonstrating the presence of the heterozygous mutation in all the eight affected and absence in all the seven unaffected individuals. This mutation was found to be absent in 676 unrelated healthy controls and 781 patients of other disease from another unpublished project of our group. CONCLUSIONS: Taken together, our results suggest that EPS8L3 is a causative gene for MUHH, which was helpful for advancing us on understanding of the pathogenesis of MUHH. Our study also has further demonstrated the effectiveness of combining exome sequencing with linkage information for identifying Mendelian disease genes.

Exome sequencing identifies MVK mutations in disseminated superficial actinic porokeratosis.

Disseminated superficial actinic porokeratosis (DSAP) is an autosomal dominantly inherited epidermal keratinization disorder whose etiology remains unclear. We performed exome sequencing in one unaffected and two affected individuals from a DSAP family. The mevalonate kinase gene (MVK) emerged as the only candidate gene located in previously defined linkage regions after filtering against existing SNP databases, eight HapMap exomes and 1000 Genomes Project data and taking into consideration the functional implications of the mutations. Sanger sequencing in 57 individuals with familial DSAP and 25 individuals with sporadic DSAP identified MVK mutations in 33% and 16% of these individuals (cases), respectively. All 14 MVK mutations identified in our study were absent in 676 individuals without DSAP. Our functional studies in cultured primary keratinocytes suggest that MVK has a role in regulating calcium-induced keratinocyte differentiation and could protect keratinocytes from apoptosis induced by type A ultraviolet radiation. Our results should help advance the understanding of DSAP pathogenesis.

Genome-wide association study identifies two new susceptibility loci for atopic dermatitis in the Chinese Han population.

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.

Association analyses identify six new psoriasis susceptibility loci in the Chinese population.

We extended our previous genome-wide association study for psoriasis with a multistage replication study including 8,312 individuals with psoriasis (cases) and 12,919 controls from China as well as 3,293 cases and 4,188 controls from Germany and the United States and 254 nuclear families from the United States. We identified six new susceptibility loci associated with psoriasis in the Chinese study containing the candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8 and ZNF816A (combined P < 5 × 10⁻8) and replicated one locus, 5q33.1 (TNIP1-ANXA6), previously reported (combined P = 3.8 × 10⁻²¹) in the European studies. Two of these loci showed evidence for association in the German study at ZNF816A and GJB2 with P = 3.6 × 10⁻³ and P = 7.9 × 10⁻³, respectively. ERAP1 and ZNF816A were associated with type 1 (early onset) psoriasis in the Chinese Han population (test for heterogeneity P = 6.5 × 10⁻³ and P = 1.5 × 10⁻³, respectively). Comparisons with the results of previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between the Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.

A novel KIT missense mutation in one Chinese family with piebaldism.

Piebaldism is an autosomal dominant disorder characterized by congenital leukoderma, mostly affecting forehead, abdomen and knee. Previous studies have revealed that piebaldism is caused by mutations of the KIT gene, which encodes the cell surface transmembrane tyrosine kinase receptor for KIT ligand. We reported here a Chinese Han family with piebaldism, and performed mutation detection of KIT gene by direct sequencing. A novel missense mutation C58G was identified in the patients, but not in the healthy individuals from the family and 100 unrelated controls. This study contributes to the database on KIT in piebaldism and enriches the knowledge about the genotype/phenotype correlation.

Psoriasis genome-wide association study identifies susceptibility variants within LCE gene cluster at 1q21.

We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).

Association of HLA-DQA1 and DQB1 alleles with keloids in Chinese Hans.

BACKGROUND: Some studies have suggested that human HLA status might potentiate development of keloids phenotype, and exists ethnic differences. No report has been published about HLA-DQA1 and DQB1 alleles associated with keloids in Chinese Hans. OBJECTIVES: To investigate whether HLA-DQA1 and DQB1 alleles are associated with genetic susceptibility to keloids in Chinese Hans. METHODS: Polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA-DQA1 and DQB1 alleles among 192 patients with keloids and 273 healthy controls in Chinese Hans. RESULTS: (1) The frequencies of HLA-DQA1*0104, DQB1*0501 and DQB1*0503 (OR = 2.13, P(c) = 0.0063; OR = 14.42, P(c) < 10(-7) and OR = 6.09, P(c) < 10(-7), respectively) were significantly higher, while the frequencies of DQA1*0501, DQB1*0201 and DQB1*0402 (OR = 0.46, P(c) = 0.0099; OR = 0.24, P(c) < 10(-4) and OR = 0.10, P(c)=0.0054, respectively) were lower in patients than in controls. (2) In this study significant susceptibility haplotypes to keloids were DQA1*0104-DQB1*0501 and DQA1*0104-DQB1*0503. (3) HLA-DQB1*0501 and DQB1*0503 were positively associated with all subgroups of keloid patients. However, the DQA1*0104 (OR = 2.51, P(c) = 0.0009; OR = 2.22, P(c) = 0.0090 and OR = 2.20, P(c) = 0.0117, respectively) was only prevalent in keloid patients with single site, moderate severity and negative family history. (4) HLA-DQB1*0201 (OR = 0.27, P(c) = 0.0018 and OR = 0.27, P(c) = 0.0012, respectively) and DQB1*0402 (OR = 0.07, P(c) = 0.0270 and OR = 0.07, P(c) = 0.0306, respectively) were negatively associated with moderate severity and negative family history in keloids, moreover, HLA-DQB1*0201 (OR = 0.23, P(c) = 0.0003) and DQA1*0501 (OR = 0.43, P(c) = 0.0234) were less prevalent in patients with single site. CONCLUSION: This study demonstrated the positive association of HLA-DQA1 and DQB1 alleles and haplotypes with keloids.

Polymorphisms in interleukin-15 gene on chromosome 4q31.2 are associated with psoriasis vulgaris in Chinese population.

Through a series of linkage analyses in a large Chinese family cohort of psoriasis, we previously identified and confirmed a non-HLA psoriasis linkage locus PSORS9 within a small region at 4q31.2-32.1. Within the critical region of the PSORS9 locus, IL-15 has been long recognized as a strong candidate gene for psoriasis. In this study, we investigated the association between IL-15 genetic polymorphisms and psoriasis in a large Chinese sample. Highly significant evidence for association was identified at a single-nucleotide polymorphism (SNP) (g.96516A --> T) within the 3'-untranslated region (UTR) of the IL-15 gene (P=0.00006, after correction for multiple testing). Haplotype analysis using the SNPs within the 3'UTR region also provided strong supporting evidence for association (P=0.00005), where we identified a haplotype of the 3'UTR region of IL-15 associated with increased risk to psoriasis (odds ratio=1.65). This association was also supported by the results of our expression activity analyses, where we demonstrated that the identified risk haplotype is associated with an increased activity of IL-15. Therefore, we provided early evidence for the important role of IL-15 genetic variants in the pathogenesis of psoriasis, probably by increasing interleukin production and inflammation in the lesions of psoriasis.

Follow-up analysis of PSORS9 in 151 Chinese families confirmed the linkage to 4q31-32 and refined the evidence to the families of early-onset psoriasis.

Psoriasis linkage to 4q28-32 (PSORS9) was initially identified by our genome-wide scan in 61 Chinese families and subsequently supported by a meta-analysis of five genome-wide linkage scans of European populations. In this study, we performed a follow-up analysis of PSORS9 using an additional 90 families and improved marker coverage. Joint analysis of all 151 families obtained significant linkage evidence (HLOD=4.53, nonparametric linkage (NPL)=4.03 (P=0.000003)) at the marker interval D4S2997-D4S3033, and the same was obtained for the analysis of the independent new families (HLOD=4.33, NPL=3.15 (P=0.00004)). The linkage evidences from the whole families and the new families exceeded the genome-wide criteria for significant linkage. Furthermore, by performing an ordered subset analysis using mean age at onset as a covariate, we demonstrated that evidence for linkage to PSORS9 is concentrated in the early-onset families and suggested that further study of PSORS9 should focus on early-onset patients. This finding is contradictory to what was found in the Icelandic population and, together with other linkage results, suggests that Chinese and European populations are genetically different for linkage to PSORS9, which may partially explain the influence of ethnic factors on the varying prevalence of psoriasis.

Five mutations of ATP2A2 gene in Chinese patients with Darier's disease and a literature review of 86 cases reported in China.

Darier's disease (DD) is an autosomal dominantly inherited skin disorder characterized by loss of adhesion between epidermal cells (acantholysis) and abnormal keratinization. To date, at least 140 mutations in the ATP2A2 gene have been identified as the genetic basis of DD. Here we reported three familial and two sporadic Chinese DD patients totally with four missense mutations (N767D, M494I, M494L, C318F) and one splice-site mutation (1288-6A-->G) in ATP2A2 gene, and presented a literature review of DD cases reported in China since 1989. Our data add new variants to the repertoire of ATP2A2 gene in DD and confirms that most mutations in the ATP2A2 gene are private and missense type. Likewise, the literature review indicates that DD is not uncommon in China and presents more information about genotype-phenotype correlations.

Inversa acne (hidradenitis suppurativa): a case report and identification of the locus at chromosome 1p21.1-1q25.3.

Acne inversa (hidradenitis suppurativa) is a chronic relapsing inflammatory skin disease characterized by recurrent draining sinuses and abscesses, predominantly in skin folds that carry terminal hairs and apocrine glands. The genetic basis for this disease is unknown. In this study, we performed a genome-wide scan in a four-generation Chinese family to map the chromosome location of the responsible gene. We first identified a locus at chromosome 1p21.1-1q25.3 with the maximum logarithm of odds (LOD) score of 3.26 at the marker D1S2624 (at recombination fraction=0.00). The other two-point LOD scores >/=3 were observed at markers D1S2695, D1S2726, D1S252, and D1S2777. Haplotype analysis localized this locus to a 76 Mb region flanked by D1S248 and D1S2711. This is the first locus for the inversa acne and will be a starting point towards understanding the molecular mechanisms of this disease.

Association of HLA class I alleles with aloplecia areata in Chinese Hans.

BACKGROUND: Some studies suggested that human HLA status may potentiate development of the AA phenotype and exists ethic differences. No report has been published about HLA class I alleles associated with AA in Chinese Hans. OBJECTIVE: To study the distribution of HLA class I alleles and haplotypes in Chinese Hans AA patients and the relation of HLA class I profile with age of onset, severity, duration of current attack, past history and family history. METHODS: The polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA class I alleles in 192 patients with AA and 252 healthy controls in Chinese Hans. RESULTS: The frequencies of HLA-A*02, -A*03, -B*18, -B*27, -B*52 and -Cw*0704 were significantly higher in patients than in controls. The A*2-B*18, A*2-B*27, A*2-B*52, A*2-Cw*0704, B*18-Cw*0704, B*27-Cw*0704, B*52-Cw*0704 were found as high-risk haplotypes in developing AA in this study. The HLA-A*02 and -A*03 were observed increased frequencies in patients less than 50% hair loss, and HLA-B*27 equally in patients of 50-99% hair loss, alopecia totalis and alopecia universalis. The frequencies of HLA-A*02 and -B*27 were significantly raised in recurrent patients, and ones of HLA-A*02, -A*03 and -B*27 similarly in patients without a positive family history. CONCLUSION: This study demonstrated the positive association of HLA class I alleles and haplotypes with AA. There may be differences in genetic background in patients with different age of onset, grade of scalp hair loss, duration of current attack, a past history and a family history.

The gene for a rare autosomal dominant form of pompholyx maps to chromosome 18q22.1-18q22.3.

Pompholyx is a rather common disorder characterized by recurrent crops of vesicles or bullae on the lateral aspects of the fingers, as well as the palms and soles with non-erythematous skin. Until now, very few large families have been reported, so no gene or locus has been identified. Here, we performed a genome-wide search in a large Chinese family to map the chromosome location of the responsible gene. We identified a locus at chromosome 18q22.1-18q22.3 with a maximum two-point LOD score of 3.61 at marker D18S1131 (theta = 0.00). Haplotype analyses indicated that the disease gene is located within 12.07 cM region between markers D18S465 and D18S1362, which corresponds to 8.0 Mb. This is the first locus identified for pompholyx. It will aid future identification of the responsible gene, which will be useful for the understanding of the molecular mechanism of pompholyx.