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Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome
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Meng-Xuan Wang, Jun Han, Teng Liu, Ren-Xue Wang, Li-Ting Li, Zhong-Die Li, Jun-Cong Yang, Lang-Li Liu, Yi Lu, Xin-Bao Xie, Jing-Yu Gong, Shi-Yu Li, Lei Zhang, Victor Ling, Jian-She Wang |
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Background: The liver manifestations of Alagille syndrome (ALGS) are highly variable, and factors affecting its prognosis are poorly understood. We asked whether the composition of bile acids in ALGS patients with good clinical outcomes differs from that in patients with poor outcomes and whether bile acids could be used as prognostic biomarkers.
Methods: Blood for bile acid profiling was collected from genetically confirmed JAG1-associated ALGS patients before one year of age. A good prognosis was defined as survival with native liver and total bilirubin (TB) < 85.5 米mol/L, while a poor prognosis was defined as either liver transplantation, death from liver failure, or TB ≡ 85.5 米mol/L at the last follow-up.
Results: We found that the concentrations of two poly-hydroxylated bile acids, tauro-2汕,3汐,7汐,12汐-tetrahydroxylated bile acid (THBA) and glyco-hyocholic acid (GHCA), were significantly increased in patients with good prognosis compared to those with poor prognosis [area under curve (AUC) = 0.836 and 0.782, respectively] in the discovery cohort. The same trend was also observed in the molar ratios of GHCA to glyco-chenodeoxycholic acid (GCDCA) and tetrahydroxylated bile acid (THCA) to tauro-chenodeoxycholic acid (TCDCA) (both AUC = 0.836). A validation cohort confirmed these findings. Notably, tauro-2汕,3汐,7汐,12汐-THBA achieved the highest prediction accuracy of 88.00% (92.31% sensitivity and 83.33% specificity); GHCA at > 607.69 nmol/L was associated with native liver survival [hazard ratio: 13.03, 95% confidence interval (CI): (2.662每63.753), P = 0.002]. Conclusions: We identified two poly-hydroxylated bile acids as liver prognostic biomarkers of ALGS patients. Enhanced hydroxylation of bile acids may result in better clinical outcomes. |
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[Abstract] [Full Text] [PDF]
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A multicenter prospective study of next-generation sequencing-based newborn screening for monogenic genetic diseases in China
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Ru-Lai Yang, Gu-Ling Qian, Ding-Wen Wu, Jing-Kun Miao, Xue Yang, Ben-Qing Wu, Ya-Qiong Yan, Hai-Bo Li, Xin-Mei Mao, Jun He, Huan Shen, Hui Zou, Shu-Yuan Xue, Xiao-Ze Li, Ting-Ting Niu, Rui Xiao, Zheng-Yan Zhao |
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Background: Newborn screening (NBS) is an important and successful public health program that helps improve the long-term clinical outcomes of newborns by providing early diagnosis and treatment of certain inborn diseases. The development of next-generation sequencing (NGS) technology provides new opportunities to expand current newborn screening methodologies.
Methods: We designed a newborn genetic screening (NBGS) panel targeting 135 genes associated with 75 inborn disorders by multiplex PCR combined with NGS. With this panel, a large-scale, multicenter, prospective multidisease analysis was conducted on dried blood spot (DBS) profiles from 21,442 neonates nationwide.
Results: We presented the positive detection rate and carrier frequency of diseases and related variants in different regions; and 168 (0.78%) positive cases were detected. Glucose-6-Phosphate Dehydrogenase deficiency (G6PDD) and phenylketonuria (PKU) had higher prevalence rates, which were significantly different in different regions. The positive detection of G6PD variants was quite common in south China, whereas PAH variants were most commonly identified in north China. In addition, NBGS identified 3 cases with DUOX2 variants and one with SLC25A13 variants, which were normal in conventional NBS, but were confirmed later as abnormal in repeated biochemical testing after recall. Eighty percent of high-frequency gene carriers and 60% of high-frequency variant carriers had obvious regional differences. On the premise that there was no significant difference in birth weight and gestational age, the biochemical indicators of SLC22A5 c.1400C > G and ACADSB c.1165A > G carriers were significantly different from those of non-carriers. Conclusions: We demonstrated that NBGS is an effective strategy to identify neonates affected with treatable diseases as a supplement to current NBS methods. Our data also showed that the prevalence of diseases has significant regional characteristics, which provides a theoretical basis for screening diseases in different regions. |
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[Abstract] [Full Text] [PDF]
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Unique mutation spectrum of progressive pseudorheumatoid dysplasia in the Chinese population: a retrospective genotype每phenotype analysis of 105 patients
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Wei Wang, Si-Hao Gao, Min Wei, Lin-Qing Zhong, Wei Liu, Shan Jian, Juan Xiao, Cai-Hui Zhang, Jian-Guo Zhang, Xiao-Feng Zeng, Wei-Bo Xia, Zheng-Qing Qiu, Hong-Mei Song |
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Background: Progressive pseudorheumatoid dysplasia (PPRD) is a rare genetic disease with autosomal recessive inheritance. There was a lack of genotype每phenotype correlation data from the Chinese population. This study aimed to identify the genotype and phenotype characteristics of Chinese PPRD patients and to conduct a genotype每phenotype analysis of Chinese PPRD patients.
Methods: Genetic analysis was performed for suspected PPRD patients from Peking Union Medical College Hospital. Medical records were collected from the electronic medical record system and patient-held portable health records. Published Chinese PPRD cases were gathered from both international and Chinese local databases. We collected demographic information, genetic variants, clinical manifestations, and imaging characteristics for further analysis.
Results: We included 105 Chinese PPRD patients in the current study. Thirty-three variants, including nine novels and five hotspot variants, were identified, with 26/33 (79%) variants exclusively seen in the Chinese population. Chinese PPRD patients share a phenotype similar to that in international reports. Joint involvement may progress with age (R2 = 0.2541). Long bone shortening and severe deformities occur in three patients with biallelic null variants, of which at least one variant is located in exon 2. Among hotspot variants, c.624dupA (p.C209Mfs*21) were associated with later onset and more involved joints. Elbow joints were more likely to be affected in patients carrying c.624dupA (p.C209Mfs*21) and c.866dupA (p.S209Efs*13). Shoulder joints are more likely to be involved in patients with biallelic null variants (P = 0.027). Conclusions: Chinese PPRD patients share a unique mutation spectrum. Among the five hotspot variants, c.624dupA is associated with later onset of disease, more extensive joint involvement, and a tendency to affect elbow joints. Biallelic null variants with at least one variant in exon 2 could be a likely cause of long bone shortening and severe deformities. |
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[Abstract] [Full Text] [PDF]
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Delayed-onset adenosine deaminase deficiency with a novel synonymous mutation and a case series from China
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Yue Zhang, Wei Liu, Zhou Shu, Yan Li, Fei Sun, Zhi-Gang Li, Tong-Xin Han, Hua-Wei Mao, Tian-You Wang |
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Background: Adenosine deaminase (ADA) is a key enzyme in the purine salvage pathway. Genetic defects of the ADA gene can cause a subtype of severe combined immunodeficiency. To date, few Chinese cases have been reported.
Methods: We retrospectively reviewed the medical records of patients diagnosed with ADA deficiency in Beijing Children*s Hospital and summarized the previously published ADA deficiency cases from China in the literature.
Results: Nine patients were identified with two novel mutations (W272X and Q202 =). Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations of Chinese ADA-deficient patients. The ADA genotype has a major effect on the clinical phenotype. Notably, a novel synonymous mutation (c.606G>A, p.Q202=) was identified in a delayed-onset patient, which affected pre-mRNA splicing leading to a frameshift and premature truncation of the protein. Furthermore, the patient showed 污汛T cells expansion with an increased effect or phenotype, which may be associated with the delayed onset of disease. In addition, we reported cerebral aneurysm and intracranial artery stenosis for the first time in ADA deficiency. Five patients died with a median age of four months, while two patients received stem cell transplantation and are alive. Conclusions: This study described the first case series of Chinese ADA-deficient patients. Early-onset infection, thymic abnormalities and failure to thrive were the most common manifestations in our patients. We identified a synonymous mutation that affected pre-mRNA splicing in the ADA gene, which had never been reported in ADA deficiency. Furthermore, we reported cerebral aneurysm in a delayed-onset patient for the first time. Further study is warranted to investigate the underlying mechanisms. |
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[Abstract] [Full Text] [PDF]
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Australian children living with rare diseases: health service use and barriers to accessing care
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Suzy Teutsch, Yvonne Zurynski, Guy D. Eslick, Marie Deverell, John Christodoulou, Helen Leonard, Troy Dalkeith, Sandra L. J. Johnson, Elizabeth J. Elliott |
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Background: Children with rare diseases experience challenges at home and school and frequently require multi-disciplinary healthcare. We aimed to determine health service utilization by Australian children with rare diseases and barriers to accessing healthcare.
Methods: Parents completed an online survey on health professional and emergency department (ED) presentations, hospitalization, and barriers to accessing services. Potential barriers to service access included residential location (city, regional, remote) and child health-related functioning, determined using a validated, parent-completed measure-of-function tool.
Results: Parents of 462 children with over 240 rare diseases completed the survey. Compared with the general population, these children were more likely to be hospitalized [odds ratio (OR) = 17.25, 95% confidence interval (CI) = 15.50每19.20] and present to the ED (OR = 4.15, 95% CI = 3.68每4.68) or a family physician (OR = 4.14, 95% CI = 3.72每4.60). Child functional impairment was nil/mild (31%), moderate (48%) or severe (22%). Compared to children with nil/mild impairment, those with severe impairment were more likely to be hospitalized (OR = 13.39, 95% CI = 7.65每23.44) and present to the ED (OR = 11.16, 95% CI = 6.46每19.27). Most children (75%) lived in major cities, but children from regional (OR = 2.78, 95% CI = 1.72每4.55) and remote areas (OR = 9.09, 95% CI = 3.03每25.00) experienced significantly more barriers to healthcare access than children from major cities. Barriers included distance to travel, out-of-pocket costs, and lack of specialist medical and other health services. Conclusions: Children with rare diseases, especially those with severe functional impairment have an enormous impact on health services, and better integrated multidisciplinary services with patient-centered care are needed. Access must be improved for children living in rural and remote settings. |
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[Abstract] [Full Text] [PDF]
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