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.

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.

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 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.

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.

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.

Identification of a novel locus for Marie Unna hereditary hypotrichosis to a 17.5 cM interval at 1p21.1-1q21.3.

Marie Unna hereditary hypotrichosis (MUHH) is a rare autosomal dominant disorder characterized by coarse, wiry, twisted hair developed in early childhood and followed by the development of alopecia. A locus for this disorder was localized to chromosome 8p, but no gene responsible for it has been identified. To map and determine whether MUHH is a genetically heterogeneous disorder and identify the disease gene locus in a four-generation Chinese family with MUHH. We performed a genome-wide scan in this family. Two-point linkage analysis was performed using Linkage programs version 5.10 software and haplotype was constructed with Cyrillic Version 2.02 software. We failed to confirm the previous locus for MUHH at chromosome 8p and obtained the conformed evidence for linkage at chromosome 1. Two-point logarithm of odds ratio scores > or =3 were observed at markers D1S2746 and D1S2881. Haplotype analysis localized this locus to a 42 Mb region. The previous results and this study have shown that MUHH is a genetically heterogeneous disorder. Our family was mapped to a 17.5 cM region between markers D1S248 and D1S2345.

Two frameshift mutations in the RNA-specific adenosine deaminase gene associated with dyschromatosis symmetrica hereditaria.

OBJECTIVE: To report and analyze the mutations of the double-stranded RNA-specific adenosine deaminase (DSRAD) gene in 2 Chinese pedigrees with dyschromatosis symmetrica hereditaria (DSH). DESIGN: Pedigree study. SETTING: Anhui province of China. PATIENTS: Two Chinese families, consisting of 19 individuals (family 1) and 5 individuals (family 2). INTERVENTIONS: We directly performed mutation detection of the DSRAD gene in 2 Chinese families with DSH by sequencing. The whole coding region of DSRAD was amplified by polymerase chain reaction, and products were analyzed by direct sequencing. MAIN OUTCOME MEASURES: Frameshift DSRAD gene mutations. RESULTS: The c.3513insC (Arg1171fs) mutation was found in all patients but not in the healthy individuals from family 1, and the c.3220_3224delGCATC (Gly1073fs) mutation was found in 2 patients but not in the healthy members of family 2. These 2 mutations were not found in 96 unrelated control individuals. CONCLUSION: Our data suggest that these 2 novel frameshift mutations in the DSRAD gene could cause DSH in the Chinese Han population and add new variants to the repertoire of DSRAD mutations in DSH.