A Pathogenic Variant p.Phe177Val in PSEN1 Causes Early-Onset Alzheimer's Disease in a Chinese Family.

Familial Alzheimer's disease (FAD) present as a positive family history of cognitive decline, with early onset and an autosomal dominant inheritance pattern. FAD is mainly caused by the mutations in the genes encoding for amyloid precursor protein (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2). In the present study, we identified a variant (c.529T > G, p.Phe177Val) in PSEN1 across three generations in a Chinese family with FAD using whole-exome sequencing. The mean age of onset was 39 years (range: 37 to 40 years) in this family. In cell transfection studies, the mutant PSEN1 protein carrying p.Phe177Val increased both the production of Aß42 and the ratio of Aß42 over Aß40, as compared to wild-type PSEN1. Our results confirm the pathogenicity of PSEN1 p.Phe177Val variant in FAD and broaden the clinical phenotype spectrum of FAD patients with PSEN1 p.Phe177Val variant.

Decentralized Privacy-Preserving Platform for Clinical Data Sharing and Analysis.

Collection and management of clinical data for administration and analysis is a time-consuming and complex task, especially when multiple data providers been involved. Even if people are willing to take on the burden for it, there is still no mature solution to protect data privacy for distributed data providers. Distributed ledger is an emerging technology that supports decentralized data sharing and management. Based on this, we present a platform which enables distributed and truthful data collection and serves privacy-preserving needs in clinical data management. Our system, built on Hyperledger Fabric, used smart contract to execute data aggregation and provide basic analysis methods. The system used ledger and world status to record data access history and other metadata. This decentralized platform enables data providers to proactively share and protect their data, Thus can simplify clinical data collection procedure and promote efficient collaboration between providers.

The Associations of PMF1, ICAM1, AGT, TRIM65, FBF1, and ACOX1 Variants With Leukoaraiosis in Chinese Population.

Background: Leukoaraiosis (LA) is shown as white matter hyperintensities on T2-weighted magnetic resonance imaging brain scans. Together with candidate gene association studies (CGAS), multiple genome-wide association studies (GWAS) have reported large numbers of single nucleotide polymorphisms (SNPs) to be associated with LA in European populations. To date, no replication studies have been reported in independent Chinese samples. Methods: Here, we performed a candidate gene association study comprising 220 Chinese subjects with LA and 50 controls. Thirty-nine polymorphisms on 32 risk genes were selected from previous studies, and they were genotyped through matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS). Genetic association analysis was firstly performed in all subjects with LA. Then, the same analysis was conducted in the six random sampling cohorts of 50 LA patients, respectively. Data analyses on the associations of SNPs with LA risk were evaluated through Pearson's χ2 and multivariate logistic regression tests. Results: We found that eight polymorphisms in six genes (PMF1, ICAM1, TRIM65, AGT, FBF1, and ACOX1) were significantly associated with LA in the genetic association tests. Except for those eight gene variants, 24 other polymorphisms were not found to be significantly associated with LA in general genetic model, dominant model, recessive model, or multiplicative model. Among those eight polymorphisms, rs2984613 in PMF1 showed significant association with LA in the cohort of 220 LA subjects, and such significant association remained in both general genetic model (OR: 0.262, 95% CI: 0.091-0.752, p adj = 0.030) and recessive model (OR: 0.323, 95% CI: 0.119-0.881, p adj = 0.038) when controlling for clinical variables. Seven other significant variants (rs5498 in ICAM1, rs699 in AGT, rs2305913 in FBF1, rs1135640 in ACOX1, and rs3760128, rs7214628, and rs7222757 in TRIM65) were identified in those six random sampling tests that were conducted in the adjusted cohorts of 50 LA patients. In addition, except for rs699 which showed detrimental effect and represented a risk variant for LA, seven other polymorphisms seemed to exert protective effects on LA and to reduce the risk of LA. It is necessary to confirm these associations in an independent cohort. Conclusions: This first replication study on multiple genes in an independent Chinese population did not replicate any risk polymorphisms for LA other than rs 699 in AGT but revealed the significantly negative associations of PMF1, ICAM1, TRIM65, FBF1, and ACOX1 polymorphisms with LA. It not only supported the strong ethnic differences in the genetics of LA but also indicated that those six identified genes may be involved in Chinese white matter lesions. Larger scales of CGAS and GWAS are necessary to confirm and decipher those ethnic-Han specific risk genes for LA in China.

Incidence and risk factors of leukoaraiosis from 4683 hospitalized patients: A cross-sectional study.

Leukoaraiosis (LA) refers to white matter hyperintensities or white matter lesions (WMLs) on magnetic resonance imaging (MRI) scans of the brain; this disease is associated with an increased risk of stroke, dementia, and cognitive decline. The aims of the study are to assess the incidence of LA and its associated risk factors in a Chinese population.A hospital-based cross-sectional study was conducted that included 4683 patients who were 40 years or older. Data collected included age, sex, hypertension, diabetes, smoking, drinking, homocysteine (HCY), and low-density lipoprotein cholesterol (LDL-C) levels in the blood in addition to brain MRI information. We examined the relationship of those putative risk factors with LA, LA occurrence, and LA progression through single-factor and multivariate analyses.Of the total subjects, 58.3% (2731/4683 cases) suffered from LA. LA was more frequent amongst elderly females, particularly in those older than 60, compared to men. The incidence of LA increased with age. Age, sex, hypertension, diabetes, smoking, and HCY levels all were risk factors for LA. Amongst those risk factors, both smoking and high HCY levels were associated with the onset process of LA. Moreover, the multivariate logistic analysis revealed that both drinking and abnormal LDL-C levels were positive regulators in the progression process of LA.This study revealed that the incidence of LA is high in hospitalized patients in China; moreover, age, sex, hypertension, diabetes mellitus, smoking, drinking, and abnormal HCY and LDL-C levels were found to be associated with overall LA risk, LA onset, or LA progression. These results provide insight into strategies for the prevention and treatment of LA.

The CELSR1 polymorphisms rs6007897 and rs4044210 are associated with ischaemic stroke in Chinese Han population.

BACKGROUND: Recently, CELSR1 was identified by genome-wide association studies (GWAS) as a susceptibility gene for ischaemic stroke (IS) in Japanese individuals. AIM: The goal was to examine whether CELSR1 variants are associated with IS in the Chinese Han population. SUBJECTS AND METHODS: This study genotyped two single nucleotide polymorphisms (SNPs) of CELSR1, rs6007897 and rs4044210, in a Chinese sample of 569 IS cases and 581 controls and assessed their genotype and allele associations with IS. RESULTS: The results showed that rs6007897 and rs4044210 variants of CELSR1 were significantly (p < 0.01) associated with IS. These associations remained after adjustment for age, gender, smoking status, hypertension, diabetes mellitus and hypercholesterolemia. In addition, a significant association was observed of rs6007897 and rs4044210 of CELSR1 with large artery atherosclerosis (LAA), a sub-type of IS (p < 0.01). CONCLUSION: Taken together, the present study has proven for the first time that CELSR1 is a susceptibility gene for IS in the Chinese Han population, especially for LAA.

X-linked glycogen storage disease IXa manifested in a female carrier due to skewed X chromosome inactivation.

BACKGROUND: Glycogen storage disease (GSD) is a group of inherited metabolic disorders due to enzymatic deficiency involved in glycogen breakdown. In various subtypes of GSD, GSD IXa is an X-linked recessive disorder, which only manifested in males. Here, we report a case of X-linked GSD IXa manifested in a female Chinese patient accompanying a skewed X-chromosome inactivation (XCI). METHODS: A 29-y-old Chinese female was admitted to evaluate mild hepatomegaly, which was repeatedly observed in serial abdominal ultrasonographic examinations. GSDIXa was suspected. To identify the mutation and the disease mechanism, we performed sequencing analysis of the PHKA2 gene, XCI assay and cDNA expression analysis. RESULTS: Sequencing analysis revealed a heterozygous mutation in the PHKA2 gene (c.3614C>T; p.P1205L) of the patient. In XCI assay, the proband showed a skewed XCI pattern cDNA expression analysis showed a preferential expression of the mutant allele in leukocytes of the patient. CONCLUSIONS: This is a rare report of X-linked GSD IXa manifested in a female carrier with skewed XCI. Skewed XCI can play a key role in the manifestation of X-linked recessive disorders in female carriers.

Follow-up examination of 12 heart transplant recipients with cardiac CT.

OBJECTIVE: The aims of this study were to observe the changes of a transplanted heart with cardiac computed tomography (CT) and to evaluate the clinical application of the examination. METHODS: Cardiac CT was performed on 12 heart transplant recipients, of which 4 cases were also examined by echocardiography. Coronary arteries, the cardiac chamber, and the wall were shown with three-dimensional imaging techniques, and their changes were analyzed and discussed. RESULTS: Twelve heart transplant recipients were successfully examined by CT. All transplanted hearts were found with good anastomosis at the great vessels and atria. Coronary allograft vasculopathy was found in 7 cases, of which 4 cases were found with ventricular dilation or ventricular septum thickening and 1 with tricuspid regurgitation. Ventricular dilation was found in other 3 cases, of which 1 was found with ventricular septum thickening and 1 with tricuspid regurgitation. No abnormality was found by cardiac CT in the rest 2 cases, which were found with mitral regurgitation by echocardiography. CONCLUSION: Cardiac CT can clearly and directly display the changes in the shape of a transplanted heart and coronary artery abnormalities. It will become an ideal noninvasive follow-up method for the heart transplant recipients.

Organochlorine isotopic pattern-enhanced detection and quantification of triclosan and its metabolites in human serum by ultra-high-performance liquid chromatography/quadrupole time-of-flight/mass spectrometry.

Organochlorines possess special isotopic patterns that obey the chlorine rule. In the case of triclosan (TCS), which contains three chlorine atoms, the isotopic patterns are composed of seven obvious peaks with the calculated masses ranging from 286.9435 to 292.9350 in negative ion mode and with specific isotopic abundance ratios of 100:13.1:97.1:12.6:31.8:4.1:3.6. In this study, mass differences between the calculated and observed m/z values for all isotopic peaks of TCS were less than 3.5 ppm in the analyses of the serum samples by ultra-high-performance liquid chromatography/quadrupole time-of-flight/mass spectrometry (UHPLC-Q-TOF/MS). Combining the characteristics described above, four metabolites were identified as sulfonated TCS, glucuronidated TCS and hydroxylated sulfonated TCS. Several novel MS techniques were applied to improve the sensitivity of quantification of TCS. The limit of detection for TCS in a 250 µL serum sample was 0.05 ng/mL, which was over twenty times lower than values obtained by the LC/triple quadrupole-MS/MS method reported in the literature. The concentration of total TCS (free and conjugated) was quantified to range from 0.15 to 217 ng/mL, whereas free TCS ranged from 0.15 to 10 ng/mL. To the best of our knowledge, this is the first report on the identification of TCS and metabolites in human serum, and it also provides the most sensitive LC/MS approach for the quantification of TCS.

Is the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene due to a founder effect in Chinese head and neck paraganglioma patients?

OBJECTIVES/HYPOTHESIS: Three Chinese patients with head and neck paragangliomas have been reported to carry the c.3G>C mutation in the succinate dehydrogenase subunit D (SDHD) gene. In addition, in our hospital, two further patients were identified who have the same mutation. It is unclear whether the c.3G>C mutation in Chinese patients is a recurrent mutation or if it is due to a founder effect. We conducted haplotype analysis on these patients to answer this question. STUDY DESIGN: Individual case-control study. METHODS: Germ-line mutations were confirmed in the patients and their families examined in this study using direct sequencing. We also constructed and analyzed haplotypes in four Chinese families. Genotype frequencies were compared to the control group. RESULTS: Three of four families shared the same haplotype, which rarely occurred in the control group. The last family shared a very short area on the physical map with the other three families. CONCLUSIONS: There is a founder effect in Chinese head and neck paraganglioma patients carrying the SDHD c.3G>C mutation.

Novel nonsense CDC73 mutations in Chinese patients with parathyroid tumors.

Hyperparathyroidism-jaw tumor syndrome (HPT-JT) is an autosomal dominant disease characterized by the occurrences of parathyroid tumors and ossifying fibroma of maxilla/mandible. It is caused by mutations in CDC73 gene and mutation carriers are at increased risk of parathyroid carcinoma. Hyperparathyroidism could be the sole manifestation. We reported two Chinese patients having parathyroid neoplasm with equivocal malignant potential and parathyroid carcinoma respectively with both germline and somatic CDC73 mutations detected. Both of them presented with severe hypercalcemia and primary hyperparathyroidism with no other HPT-JT associated tumors and negative family history. We identified one novel germline mutation CDC73 NM_024529.4: c.1475G > A; NP_078805.3: p.Trp492X and one novel somatic mutation CDC73 NM_024529.4: c.142G > T; NP_078805.3: p.Glu48X. The other germline mutation CDC73 NM_024529.4: c.226C > T; NP_078805.3: p.Arg76X and somatic mutation CDC73 NM_024529.4: c.85delG; NP_078805.3: p.Glu29SerfsX8 were previously reported. This is the first report of CDC73 mutations in the Chinese population. Genetic analysis is reliable to confirm the underlying hereditary basis of hyperparathyroidism. By identification of mutations, the patient and the family members could benefit from regular surveillance for early detection of tumors.

Fatal viral infection-associated encephalopathy in two Chinese boys: a genetically determined risk factor of thermolabile carnitine palmitoyltransferase II variants.

Influenza-associated encephalopathy (IAE) is a potentially fatal neurological complication of influenza infection usually in the presence of high and persistent fever. Thermolabile carnitine palmitoyltransferase II enzyme (CPT-II) predisposes IAE, so far only described in Japanese. As the genetic origins of Japanese and Chinese are alike, similar genetic risk factors in CPT-II are expected. We report the first two unrelated Chinese patients of thermolabile CPT-II variants that underlain the persistent high fever-triggered viral infection-associated encephalopathy, multi-organ failure and death. Elevated (C16:0+C18:1)/C2 acylcarnitines ratio and the CPT2 susceptibility variant allele [p.Phe352Cys; p.Val368Ile] were detected. The asymptomatic family members of one patient also had abnormal long-chain acylcarnitines. In our experience of biochemical genetics, the elevated (C16:0+C18:1)/C2 acylcarnitines ratio is unusual and specific for thermolabile CPT-II variants. Allele frequency of [p.Phe352Cys; p.Val368Ile] among Hong Kong Chinese was 0.104, similar to Japanese data, and [p.Phe352Cys] has not been reported in Caucasians. This may explain the Asian-specific phenomenon of thermolabile CPT-II-associated IAE. We successfully demonstrated the thermolabile CPT-II variants in patients with viral infection-associated encephalopathy in another Asian population outside Japanese. The condition is likely under-recognized. With our first cases, it is envisaged that more cases will be diagnosed in subsequent years. The exact pathogenic mechanism of how other factors interplay with thermolabile CPT-II variants and high fever leading to IAE, is yet to be elucidated. Fasting and decreased intake during illness may aggravate the disease. Further studies including high risk and neonatal screening are warranted to investigate its expressivity, penetrance and temperature-dependent behaviors in thermolabile CPT-II carriers. This may lead to discovery of the therapeutic golden window by aggressive antipyretics and L-carnitine administration in avoiding the high mortality and morbidity of IAE.

Molecular basis of von Hippel-Lindau syndrome in Chinese patients.

BACKGROUND: Von Hippel-Lindau (VHL) syndrome is an autosomal dominant familial cancer syndrome predisposing the affected individuals to multiple tumours in various organs. The genetic basis of VHL in Southern Chinese is largely unknown. In this study, we characterized the mutation spectrum of VHL in nine unrelated Southern Chinese families. METHODS: Nine probands with clinical features of VHL, two symptomatic and eight asymptomatic family members were included in this study. Prenatal diagnosis was performed twice for one proband. Two probands had only isolated bilateral phaeochromocytoma. The VHL gene was screened for mutations by polymerase chain reaction, direct sequencing and multiplex ligation-dependent probe amplification (MLPA). RESULTS: The nine probands and the two symptomatic family members carried heterozygous germline mutations. Eight different VHL mutations were identified in the nine probands. One splicing mutation, NM_000551.2: c.463+1G > T, was novel. The other seven VHL mutations, c.233A > G [p.Asn78Ser], c.239G > T [p.Ser80Ile], c.319C > G [p.Arg107Gly], c.481C > T [p.Arg161X], c.482G > A [p.Arg161Gln], c.499C > T [p.Arg167Trp] and an exon 2 deletion, had been previously reported. Three asymptomatic family members were positive for the mutation and the other five tested negative. In prenatal diagnosis, the fetuses were positive for the mutation. CONCLUSIONS: Genetic analysis could accurately confirm VHL syndrome in patients with isolated tumours such as sporadic phaeochromocytoma or epididymal papillary cystadenoma. Mutation detection in asymptomatic family members allows regular tumour surveillance and early intervention to improve their prognosis. DNA-based diagnosis can have an important impact on clinical management for VHL families.

Clinical value of three-dimensional CT angiography in diagnosing blood vessel diseases / 中国基层医药

ObjectiveTo valuate the three-dimensional CT angiography(3DCTA) in diagnosing blood vessel diseases.MethodsCTA findings of 284 patients confirmed with blood vessel diseases were retrospectively analyzed.They were divided into two groups:141 cases of head and neck and 143 cases of trunk and extremities.Scan was performed with the beam collimation of 0.625 ～ 3.0mm,increment of 0.3 ～ 1.4mm,pitch of 1.0 ～ 1.5,with the gross contrast medium of 1.5 ～ 2.0ml/kg.3D imaging methods included volume rendering(VR),multi-planar reformatting (MPR),curved planar reformatting(CPR),surface shade display(SSD),maximum intensity project(MIP) and virtual endoscopy(VE).The diagnostic results of CTA were compared with those of DSA and/or surgery.ResultsIn this study,3D images of vasculature met the diagnostic criterion.The diagnostic sensitivity,specificity and accuracy of CTA was 97.28％,82.35％ and 96.48％,respectively.The size of artery aneurysm shown with CTA and DSA had no significant difference( P ＞0.05 ),both smaller than that in surgery( P ＜ 0.05 ).Conclusion3DCTA could be used in diagnosing the cardiovascular diseases and compensate the limitation of conventional CT.It had the characteristics of non-invasion,high accuracy and could partly substitute DSA.

Microarrays for personalized genomic medicine.

The combination of single nucleotide polymorphisms (SNPs) database and high-density SNP array allows the use of SNPs as informative polymorphic markers for Mendelian diseases with complex traits efficiently. With the high-density and high-resolution SNP arrays, we can detect even the smallest structural changes that would have been missed with conventional low-density cytogenetic techniques for prognostic and diagnostic utilities. Accurate mapping may be useful for genotype-phenotype correlation in individual basis and for prenatal investigations. Here, we review some applications of genome-wide SNP genotyping on detecting homozygous candidate region in consanguineous family priors to mutation analysis. In addition to personalized genomic medicine, studying the genetic heterogeneity in diverse ancestral population helps to implementing effective clinical management.

Maternally inherited Leigh syndrome: an unusual cause of infantile apnea.

INTRODUCTION: Leigh Syndrome is an uncommon cause of infantile apnea. CASE SUMMARY: We report a 5-month-old girl with sudden respiratory arrest followed by episodic hyper- and hypo-ventilation, encephalopathy, and persistent lactic acidosis. Computed tomography of the brain revealed symmetric low densities over the basal ganglia, internal capsule, thalami, and midbrain. Cardiac echocardiogram was suggestive of hypertrophic cardiomyopathy. DISCUSSION: Diagnosis of Leigh syndrome due to T8993G mutation was confirmed with polymerase chain reaction and direct DNA sequencing of mitochondrial genome. To our knowledge, this is the first report of proven maternally inherited Leigh syndrome in Hong Kong.

Can baseline magnetic resonance angiography (MRA) status become a foremost factor in selecting optimal acute stroke patients for recombinant tissue plasminogen activator (rt-PA) thrombolysis beyond 3 hours?

OBJECTIVE: We investigated whether baseline vessel status evaluated by magnetic resonance angiography (MRA) can be the foremost factor to classify acute ischemic stroke patients into subgroups for thrombolytic therapy within 3-6 hours of symptom onset. METHODS: Acute ischemic stroke patients beyond 3 hours after symptom onset were examined by stroke magnetic resonance imaging (MRI) (diffusion- and perfusion-weighted imaging, and MRA) before and after thrombolysis treatment within 24-48 hours. Stroke MRI was used to classify acute ischemic stroke patients into subgroups and select optimal patients for thrombolytic treatment. Clinical scores were compared to determine whether there were significant differences among subgroups. RESULTS: The difference in day 90 modified Rankin scale (mRS) between treated salvageable and untreated salvageable patients with recombinant tissue plasminogen activator (rt-PA) was remarkably statistically significant (p=0.02). Treated salvageable patients had more favorable clinical outcomes as compared with the untreated salvageable patients. Patients who did not have baseline artery occlusion were associated with more favorable clinical outcomes than untreated salvageable patients (p<0.001). The difference between treated salvageable and patients without artery occlusion in 90 day mRS score was not statistically significant (p=0.058). CONCLUSION: Baseline vessel status evaluated by MRA may be used as the first factor ahead of mismatch to categorize acute ischemic stroke patients into subgroups. Patients who do not have initial vessel occlusion may not need thrombolytic therapy.

WITHDRAWN: Novel missense mutation (Y24H) in the G6PT1 gene causing glycogen storage disease type 1b.

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Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: identification of 17 novel mutations and its genetic heterogeneity.

Wilson disease (WD), an autosomal recessive disorder of copper transport, is the most common inherited liver disorder in Hong Kong Chinese. This was the first local study to elucidate the molecular basis and establish an effective DNA-based diagnostic protocol. The ATP7B genes of 65 patients were amplified by polymerase chain reaction (PCR) and sequenced. Haplotype analysis was performed using D13S301, D13S314, and D13S316. The p.L770L/p.R778L status in 660 subjects was determined to estimate WD prevalence. Allele age of p.R778L was determined by the smallest homozygosity region between D13S301 and D13S270. We identified 42 different mutations with 17 being novel. p.R778L (17.3%) was the most prevalent. Exons 2, 8, 12, 13, and 16 harbored 70% mutations. Thirty-two haplotypes were associated with WD chromosomes. The estimated prevalence rate was 1 in 5,400. Three out of 660 normal subjects had p.L770L/p.R778L. In the remaining 657 individuals, neither p.L770L nor p.R778L was found. We characterized a Hong Kong Chinese-specific ATP7B mutation spectrum with great genetic diversity. Exons 2, 8, 12, 13, and 16 should be screened first. The perfect linkage disequilibrium suggested that p.R778L and its private polymorphism p.L770L originated from a single ancestor. This East-Asian-specific mutation p.R778L/p.L770L is aged at least 5,500 years.

Erratum to: Mutational analysis of 65 Wilson disease patients in Hong Kong Chinese: Identification of 17 novel mutations and its genetic heterogeneity.

The correct name of the eighth author should be given as Sik-To Lai, not Jak-Yiu Lai.