A novel pathogenic frameshift variant unmasked by a large de novo deletion at 13q21.33-q31.1 in a Chinese patient with neuronal ceroid lipofuscinosis type 5.

BACKGROUND: Neuronal ceroid lipofuscinosis type 5 (CLN5) is a rare form of neuronal ceroid lipofuscinoses (NCLs) which are a group of inherited neurodegenerative diseases characterized by progressive intellectual and motor deterioration, visual failure, seizures, behavioral changes and premature death. CLN5 was initially named Finnish variant late infantile NCL, it is now known to be present in other ethnic populations and with variable age of onset. Few CLN5 patients had been reported in Chinese population. CASE PRESENTATION: In this paper, we report the symptoms of a Chinese patient who suffer from developmental regression and grand mal epilepsy for several years. The DNA was extracted from peripheral blood of proband and both parents, and then whole exome sequencing was performed using genomic DNA. Both sequence variants and copy number variants (CNVs) were analyzed and classified according to guidelines. As the result, a novel frameshift mutation c.718_719delAT/p.Met240fs in CLN5 and a de novo large deletion at 13q21.33-q31.1 which unmasked the frameshift mutation were identified in the proband. Despite the large de novo deletion, which can be classified as a pathogenic copy number variant (CNV), the patient's clinical presentation is mostly consistent with that of CLN5, except for early developmental delay which is believed due to the large deletion. Both variants were detected simultaneously by exome sequencing. CONCLUSIONS: This is the first report of whole gene deletion in combination with a novel pathogenic sequence variant in a CLN5 patient. The two mutations detected with whole exome sequencing simultaneously proved the advantage of the sequencing technology for genetic diagnostics.

Association of the NQO1 C609T polymorphism with Alzheimer's disease in Chinese populations: a meta-analysis.

Several molecular genetics studies have investigated the association of NQO1 C609T polymorphism with Alzheimer's disease (AD) susceptibility in Chinese populations; however, the findings are inconclusive. To investigate the association, we performed the present meta-analysis of 5 case-control studies (including 735 AD cases and 828 controls). We searched literature from PubMed, Embase, HuGNet and CNKI databases for eligible articles that evaluated the association between NQO1 C609T polymorphism and AD risk. We used odds ratios (ORs) with 95% confidence intervals (CIs) to evaluate the strength of the association. Overall, C609T polymorphism was significantly associated with an increased AD risk (homozygote: OR = 1.87, 95% CI = 1.39-2.51, P = 0.000; heterozygote: OR = 1.93, 95% CI = 1.22-3.06, P = 0.019; dominant: OR = 1.97, 95% CI = 1.25-3.12, P = 0.004). When stratified by source of control, significant results were observed in subjects of population-based (PB), whereas no increased risk was observed among the hospital-based (HB). When stratified by APOEϵ4 carrier status, no effect of the NQO1 C609T polymorphism was seen in subjects of APOEϵ4 carriers and APOEϵ4 non-carriers. In conclusion, our results showed that NQO1 C609T polymorphism increases the risk of AD in Chinese populations. Larger studies with different ethnic populations are required to validate our findings.

Lack of association of INS VNTR polymorphism with polycystic ovary syndrome: a meta-analysis.

PURPOSE: An association between the INS VNTR polymorphisms and polycystic ovary syndrome (PCOS) susceptibility has been reported in previous studies, but the results were inconsistent. This study was conducted to explore this association using meta-analysis. METHODS: PubMed, Embase, and China National Knowledge Infrastructure (CNKI) were searched according to predefined criteria for all relevant studies published up to August 2013. Four genetic models, together with odds ratios (ORs) and 95 % confidence intervals (CI), were calculated. Subgroup analyses were performed by ethnicity, anovulatory PCOS, and Hardy-Weinberg equilibrium (HWE) in the controls. RESULTS: In total, 13 case-control studies, including 1,767 cases and 4,108 controls, were included. No significant association was detected in overall population in all models (III/III vs. I/I: OR = 1.200, 95%CI = 0.866-1.664, P=0.277; I/III vs. I/I: OR = 1.041, 95%CI = 0.880-1.232, P=0.637; III/III + I/III vs. I/I: OR = 1.191, 95%CI = 0.912-1.554, P=0.199; III/III vs. I/III + I/I: OR = 1.100, 95%CI = 0.816-1.484, P=0.531), the same as in Caucasian and Asian populations. When the studies were limited to conform to HWE, the results remained persistent and robust. The anovulation subgroup showed significantly elevated risk in the I/III vs. I/I (OR = 1.460, 95%CI = 1.017-2.095, P=0.040). CONCLUSIONS: This meta-analysis revealed no significant association between INS VNTR polymorphisms and the risk of PCOS in the overall population, while it supported that variance may be associated with susceptibility to PCOS with anovulation. Further confirmation is needed from more well-designed and larger studies.

Novel and recurrent ASPM mutations of founder effect in Chinese population.

PURPOSE: Mutations in ASPM are the most common causes of primary microcephaly (MCPH), which is a rare brain developmental disorder with few studies in Chinese population so far. This study aimed to identify the common pathogenic variants of ASPM and estimated the incidence of MCPH5 in Guangxi population. METHODS: We ascertained six MCPH cases caused by ASPM mutations in Guangxi Zhuang Autonomous Region, Whole-exome sequencing (WES) was performed to uncover the causal variants. The haplotype analysis was used to estimate the age of the recurrent variation. RESULTS: Five different pathogenic variants were identified in this batch of MCPH5 cases, including two novel variants p.Ser842fs*9 and p.Lys1340Argfs*29. An rarely reported pathogenic variant, c.1789C>T/p.Arg597* was found to be a founder mutation in local population. We evaluated all ASPM variants detected among 2674 non-microcephalic individuals and estimated the MCPH5 incidence to be 5.03/1,000,000 in Guangxi population. CONCLUSIONS: We reported the first case series of Chinese MCPH cases with ASPM mutation and revealed a highly recurrent founder mutation in this local population. MCPH5 may be the major type of congenital microcephaly in Chinese population.

Genetic polymorphisms in complement receptor 1 gene and its association with HBV-related liver disease: A case-control study.

BACKGROUND: Several investigators have reported that complement receptor 1 (CR1) likely play a role in the pathogenesis of tumors, autoimmune and inflammatory diseases. However, the association of genetic polymorphisms of CR1 with risk of hepatitis B virus (HBV)-related liver disease remains unexplored. METHODS: In a case-control study of 399 HBV-related liver disease patients and 227 healthy controls, we genotyped two SNPs in CR1 (rs3811381 and rs2274567) and assessed their associations with risk of HBV-related liver disease. RESULTS: No significant differences were observed in the frequency distribution of genotypes or alleles between CR1 rs3811381 and rs2274567 polymorphisms in patients and controls. However, stratification analysis indicated that these two CR1 polymorphisms may contribute to the risk of HBV- hepatocellular carcinoma (HCC) and chronic hepatitis B (CHB) in subgroups of males, alcohol drinkers and nonsmokers. Further, our results showed that the rs3811381 polymorphism may contribute to HBV-HCC risk in subgroups of older and younger subjects, while the G allele, AG and the combined AG + GG genotypes of rs2274567 may be risk factors for HBV-HCC in younger subjects. In addition, our results indicated that subjects who carried the rs3811381 G allele and the rs2274567 AG genotype were at decreased risk of HBV- liver cirrhosis (LC) in subgroups of females. CONCLUSIONS: Our results support the hypothesis that the CR1 gene rs3811381 and rs2274567 polymorphisms may contribute to HBV-HCC and HBV-CHB risk, particularly in subgroups of males, alcohol drinkers, nonsmokers, while these two CR1 polymorphisms were found to associate with decreased risk of HBV-LC, particularly in females. Further validation of these results is warranted.

Association between catalase gene polymorphisms and risk of chronic hepatitis B, hepatitis B virus-related liver cirrhosis and hepatocellular carcinoma in Guangxi population: a case-control study.

Reactive oxygen species (ROS) play critical roles in hepatocarcinogenesis. The catalase (CAT) enzyme is involved in the repair of ROS. Therefore, we investigate the association between CAT gene polymorphisms and the risk of hepatocellular carcinoma (HCC). A total of 715 subjects were divided into 4 groups: 111 chronic hepatitis B (CHB) patients, 90 hepatitis B virus (HBV)-related liver cirrhosis (LC) patients, 266 HBV-HCC patients, and 248 healthy controls. The polymerase chain reaction-restriction fragment length polymorphism strategy was used to detect CAT gene rs1001179, rs769217, and rs7943316 polymorphisms. Binary logistic regression analyses adjusting for sex, age, ethnicity, smoking and alcohol consumption, and body mass index suggested that subjects carrying the rs769217 T allele were at marginally increased risk of CHB, LC, and HCC, with adjusted odds ratios (ORs) of 1.51 (95% confidence interval [CI] = 1.04-2.20, P = 0.029), 1.48 (95% CI = 1.03-2.14, P = 0.035), and 1.51 (95% CI = 1.14-1.98, P = 0.004), respectively. Similarly, those individuals carrying the rs769217 TT genotype had a moderately increased risk of CHB, LC, and HCC, with adjusted ORs of 2.11 (95% CI = 1.05-4.22, P = 0.035), 2.00 (95% CI, 1.01-3.95, P = 0.047), and 1.93 (95% CI = 1.14-3.28, P = 0.015), respectively. Moreover, subjects carrying the rs769217 CT genotype and at least 1 copy of the T allele (dominant model) were 1.78 times and 1.83 times more likely to develop HCC, respectively (OR = 1.78, 95% CI = 1.16-2.73, P = 0.009 and OR = 1.83, 95% CI = 1.23-2.71, P = 0.003). This association between CAT rs769217 T alleles and HCC risk is significantly strengthened among men, nonsmokers, nondrinkers, and among individuals <50 years of age. Furthermore, we found 1 high-risk haplotype GTA for CHB (OR = 1.45, 95% CI = 1.05-2.01) and 1 protective haplotype GCA for HCC risk (OR = 0.67, 95% CI = 0.52-0.87). We did not found any significant difference in CAT rs1001179 and rs7943316 polymorphisms between controls and cases. Our findings suggest that the CAT rs769217 T allele is associated with increased risk of CHB, HBV-LC, and HBV-HCC in Guangxi population.

Meta-analysis of the association between CR1 polymorphisms and risk of late-onset Alzheimer's disease.

CR1 polymorphisms have been reported to be associated with late-onset Alzheimer's disease (LOAD) susceptibility. The findings of these studies, however, have been inconsistent. Therefore, we performed a meta-analysis to assess the association between CR1 variants and LOAD susceptibility. We retrieved all relevant studies of the associations between CR1 polymorphisms and the susceptibility to LOAD for the period up to March 30, 2014. The strength of the association between CR1 polymorphisms and LOAD risk was estimated by odds ratios (ORs) and their 95% confidence intervals (CIs). A total of 6 articles were eventually identified with 2752 LOAD cases and 2313 controls for the rs6656401 polymorphism, and 4 studies containing 2547 LOAD cases and 2338 controls were included for the rs3818361 polymorphism. Overall, the pooled data showed that the CR1 rs6656401 polymorphism was significantly associated with LOAD risk in the overall population (A vs. G: OR=1.32, 95%CI=1.17-1.50, P=0.000; AG+AA vs. GG: OR=1.39, 95%CI=1.20-1.61, P=0.000). With respect to the CR1 rs3818361 polymorphism, a statistically significant increased LOAD risk was observed in the overall population (T vs. C: OR=1.24, 95% CI=1.13-1.37, P=0.000; TT+TC vs. CC: OR=1.30, 95% CI=1.15-1.46, P=0.000; TT vs. TC+CC: OR=1.35, 95% CI=1.06-1.71, P=0.014). This meta-analysis demonstrated significant associations of both the CR1 rs6656401 and CR1 rs3818361 polymorphisms with LOAD susceptibility.