Publications by authors named "Tengyan Li"

22 Publications

  • Page 1 of 1

Analysis of CNVs of CFTR gene in Chinese Han population with CBAVD.

Mol Genet Genomic Med 2020 11 19;8(11):e1506. Epub 2020 Sep 19.

Graduate School of Peking Union Medical College, Beijing, P. R. China.

Background: Congenital bilateral absence of vas deferens (CBAVD) is an important disease of male infertility, which affects 1%-2% of infertile population. In addition to common mutations of CFTR, copy number variants (CNVs) have also been implicated as one of the pathogenesis of CBAVD. The present study aimed to investigate the genetic contribution of CFTR CNVs in Chinese Han population with CBAVD.

Methods: Two hundred and sixty-three CBAVD patients were recruited. Genomic DNA was extracted from peripheral blood samples. The Multiplex Ligation-dependent Probe Amplification assay was performed which targets the region of the CFTR gene.

Results: Among 263 Chinese men affected with CBAVD in this study, 5 (1.90%) patients were detected for copy number variants in the region of CFTR gene (4 of them carried partial deletions and 1 of them carried partial duplication of CFTR gene).

Conclusions: The study showed that the rate of CFTR CNVs in Chinese population with CBAVD were basically consistent with the previous reports. And the study first revealed genetic risk of CNVs of CFTR on a large sample size of CBAVD patients in Chinese Han population, which prompted that it was necessary to detect CNVs of CFTR in Chinese Han people with CBAVD.
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http://dx.doi.org/10.1002/mgg3.1506DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7667304PMC
November 2020

Serum Metabolic Profiling Analysis of Gout Patients Treated with Traditional Chinese Medicine Tongfengtai Granules Based on Gas Chromatography-Mass Spectrometry.

Evid Based Complement Alternat Med 2020 26;2020:7404983. Epub 2020 Apr 26.

Graduate School, Peking Union Medical College, Beijing, China.

Gout has become a public health problem that seriously threatens human health. Traditional Chinese medicines (TCMs) have a long history of treating gout and have some advantages compared with the conventional medicines. Compound TCM Tongfengtai granules are gradually being used for clinical treatment of gout, but its mechanism is still unclear. The purpose of this study was to explore the metabolic profiling of serum from gout patients before and after treatment with Tongfengtai granules and identify the differential metabolites and related metabolic pathways. A total of 40 gout patients hospitalized in Shenzhen Traditional Chinese Medicine Hospital from 2018 to March 2019 were recruited in the current study, and serum samples from these patients before and after treatment with Tongfengtai granules were collected. Gas chromatography-mass spectrometry (GC-MS) assay was used to identify serum metabolites. The OPLS-DA VIP method was used to screen for potential metabolic biomarkers, and MetaboAnalyst 4.0 was used to identify related metabolic pathways. The result showed that there was a significant difference in the concentrations of six metabolites in the serum after treatment: D-galactose, lactic acid, 3-hydroxybutyric acid, D-pyran (type) glucose, alanine, and L-isoleucine. Except D-pyran (type) glucose, the serum concentrations of the other five metabolites were all significantly reduced. Besides, pathway enrichment analysis found that these potential metabolic biomarkers were mainly involved in lactose degradation and the glucose-alanine cycle. Thus, the serum metabolic profiling of gout patients treated with Tongfengtai granules changed, and the differential metabolites and related metabolic pathways might provide clues for understanding the mechanism of Tongfengtai granules.
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http://dx.doi.org/10.1155/2020/7404983DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7201437PMC
April 2020

Rare homozygous mutation in TUBB8 associated with oocyte maturation defect-2 in a consanguineous mating family.

J Ovarian Res 2020 Apr 21;13(1):42. Epub 2020 Apr 21.

Graduate School of Peking Union Medical College, Beijing, China.

Purpose: Variations in many genes may lead to the occurrence of oocyte maturation defects. To investigate the genetic basis of oocyte maturation defects, we performed clinical and genetic analysis of a pedigree.

Methods: The proband with oocyte maturation defect-2 receiving ovulation induction therapy and her parents were selected for clinical detection, whole exome sequencing and Sanger sequencing. One unrelated healthy woman received ovulation induction therapy as control. Mutations were assessed after frequency screening of public exome databases. Then homozygous variants shared by the proband and her parents were selected.

Results: Arrest of oocytes maturation was observed. A new missense mutation in TUBB8 (TUBB8: NM_177,987: exon 2: c. C161T: p. A54V) was identified, which was shown to be rare compared with public databases. The variant was highly conserved among primates, and was suggested to be deleterious by online software prediction.

Conclusions: The homozygote of this variant (TUBB8: NM_ 177,987: exon 2:c.C161T: p.A54V) might affect spindle assembly, cause arrest of oocyte maturation and lead to oocyte maturation defect-2.
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http://dx.doi.org/10.1186/s13048-020-00637-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7175565PMC
April 2020

NOTCH2 variant D1853H is mutated in two non-syndromic premature ovarian insufficiency patients from a Chinese pedigree.

J Ovarian Res 2020 Apr 20;13(1):41. Epub 2020 Apr 20.

Central Laboratory, Beijing Obstetrics and Gynecology Hospital, Capital Medical University, Chaoyang, Beijing, 100026, China.

Background: Premature ovarian insufficiency (POI) is a severe disorder of female infertility, characterized by 4-6 months of amenorrhea before the age of 40 years, with elevated follicle stimulating hormone (FSH) levels (> 25 IU/L). Although several genes have been reported to contribute to the genetic basis of POI, the molecular mechanism of POI remains unclear.

Methods: Whole-exome sequencing (WES) was performed. Sanger sequencing was carried out to validate the variant in the proband and her mother. In silico algorithms were used to analyze the mutational effect of the variant. Protein 3D structural modeling was used for predicting mutated protein structures. Vector construction and plasmids transfection were performed, and subsequently RNA-sequencing (RNA-seq) was carried out in each group to dissect the differentially expressed genes in wild-type (WT) and D1853H NOTCH2 mutant expressing groups. Gene Ontology analysis was also used to analyze the enriched biological processes or pathways among the differentially expressed genes.

Results: We report two non-syndromic POI patients from a Chinese pedigree. The FSH level of the proband (the daughter) was 46 IU/L at the age of 22. Her menarche was at the age of 12, but she was amenorrhea at the age of 20. By WES, a rare heterozygous variant (c.5557G > C;p.D1853H) in the NOTCH2 gene was identified. In silico analysis suggested that p.D1853H was a pathogenic allele. Protein 3D structural modeling suggested that D1853H may enhance or weaken the electrostatic surface potential. By molecular analysis, we found that cells expressing the D1853H NOTCH2 mutant had similar effect in activating the NOTCH signaling pathway downstream target genes. However, 106 protein-coding genes were differentially expressed between D1853H expressing cells and WT NOTCH2 expressing cells, and these genes were enriched for collagen degradation, NCAM1 interactions and HDACs deacetylate histones, revealing a unknown underlying mechanism of the pathology that leads to POI.

Conclusions: We conclude that the rare heterozygous variant in NOTCH2 may be associated with POI. This finding provides researchers and clinicians with a better understanding of the etiology, molecular mechanism and genetic consulting of POI.
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http://dx.doi.org/10.1186/s13048-020-00645-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7171760PMC
April 2020

New Gene Variants Associated with the Risk of Chronic HBV Infection.

Virol Sin 2020 Aug 15;35(4):378-387. Epub 2020 Apr 15.

Department of Infectious Diseases, Peking University First Hospital, Beijing, 100034, China.

Some patients with chronic hepatitis B virus (HBV) infection failed to clear HBV, even persistently continue to produce antibodies to HBV. Here we performed a two stage genome wide association study in a cohort of Chinese patients designed to discover single nucleotide variants that associate with HBV infection and clearance of HBV. The first stage involved genome wide exome sequencing of 101 cases (HBsAg plus anti-HBs positive) compared with 102 control patients (anti-HBs positive, HBsAg negative). Over 80% of individual sequences displayed 20 × sequence coverage. Adapters, uncertain bases > 10% or low-quality base calls (> 50%) were filtered and compared to the human reference genome hg19. In the second stage, 579 chronic HBV infected cases and 439 HBV clearance controls were sequenced with selected genes from the first stage. Although there were no significant associated gene variants in the first stage, two significant gene associations were discovered when the two stages were assessed in a combined analysis. One association showed rs506121-"T" allele [within the dedicator of cytokinesis 8 (DOCK8) gene] was higher in chronic HBV infection group than that in clearance group (P = 0.002, OR = 0.77, 95% CI [0.65, 0.91]). The second association involved rs2071676-A allele within the Carbonic anhydrase (CA9) gene that was significantly elevated in chronic HBV infection group compared to the clearance group (P = 0.0003, OR = 1.35, 95% CI [1.15, 1.58]). Upon replication these gene associations would suggest the influence of DOCK8 and CA9 as potential risk genetic factors in the persistence of HBV infection.
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http://dx.doi.org/10.1007/s12250-020-00200-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7462954PMC
August 2020

A rare frameshift variant in trans with the IVS9-5T allele of CFTR in a Chinese pedigree with congenital aplasia of vas deferens.

J Assist Reprod Genet 2019 Dec 10;36(12):2541-2545. Epub 2019 Nov 10.

Center for Genetics, National Research Institute for Family Planning, No. 12 Dahuisi Road, Haidian District, Beijing, 100081, People's Republic of China.

Purpose: Congenital aplasia of vas deferens (CAVD) is an atypical form of cystic fibrosis (CF) and causes obstructive azoospermia and male infertility. Compound heterozygous variants of CFTR are the main cause of CAVD. However, most evidence comes from genetic screening of sporadic cases and little is from pedigree analysis. In this study, we performed analysis in a Chinese pedigree with two CAVD patients in order to determine the genetic cause of this familial disorder.

Methods: In the present study, we performed whole-exome sequencing and co-segregation analysis in a Chinese pedigree involving two patients diagnosed with CAVD.

Results: We identified a rare frameshift variant (NM_000492.3: c.50dupT;p.S18Qfs*27) and a frequent CBAVD-causing variant (IVS9-TG13-5T) in both patients. The frameshift variant introduced a premature termination codon and was not found in any public databases or reported in the literature. Co-segregation analysis confirmed these two variants were in compound heterozygous state. The other male members, who harbored the frameshift variant and benign IVS9-7T allele, did not have any typical clinical manifestations of CF or CAVD.

Conclusion: Our findings may broaden the mutation spectrum of CFTR in CAVD patients and provide more familial evidence that the combination of a mild variant and a severe variant in trans of CFTR can cause vas deferens malformation.
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http://dx.doi.org/10.1007/s10815-019-01617-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6911126PMC
December 2019

Novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation in a consanguineous Chinese family with premature ovarian insufficiency.

Fertil Steril 2019 09 4;112(3):569-576.e2. Epub 2019 Jul 4.

Reproductive Medicine Center, Department of Obstetrics and Gynecology, First Affiliated Hospital of Anhui Medical University, Hefei, People's Republic of China; Anhui Province Key Laboratory of Reproductive Health and Genetics, Biopreservation and Artificial Organs, Hefei, People's Republic of China; Anhui Provincial Engineering Research Center, Anhui Medical University, Hefei, People's Republic of China. Electronic address:

Objective: To explore the candidate pathogenic gene in a premature ovarian insufficiency (POI) proband from a consanguineous marriage and detect the potential effects of mutation on cellular energy metabolism.

Design: Genetic and functional studies.

Setting: Reproductive medicine center.

Patient(s): A patient with POI, from a consanguineous family, and her family members were recruited from the Reproductive Center of the First Affiliated Hospital of Anhui Medical University.

Intervention(s): Whole exome sequencing (WES) was performed for the proband. Variation revealed by WES sequencing was validated by Sanger sequencing in her family. Sequencing data were combined with those of other sporadic cases listed in public databases to identify the causative gene.

Main Outcome Measure(s): Rare homozygous nonsynonymous variants were identified and included in subsequent analysis. Metabolic analyzes were performed using Seahorse XFe96 analyzers to measure oxygen consumption and then obtain further results of ATP production and extracellular acidification rate. The differences in energy metabolism measurements between wild type and mutation were analyzed and compared.

Result(s): A novel alanyl-tRNA synthetase 2 (AARS2) homozygous mutation (NM_020745: exon2: c.337G>C: p. G113R) was identified in the aminoacylation region using WES. The mutation was highly conserved among species and predicted to be disease causing. AARS2 encodes mitochondrial alanyl-tRNA synthetase, which attaches alanine onto tRNA-ala. AARS2 mutations were previously reported in female leukodystrophy patients with POI. In mitochondrial stress tests, the ATP productions of the mutation group (3.58 ± 0.46 fmol/min/cell) was significantly lower than that of the wild type group (6.96 ± 1.56 fmol/min/cell).

Conclusion(s): This is the first report of a homozygous pathogenic AARS2 mutation in POI. This mutation may lead to incorrect aminoacylation of tRNA, affect mitochondrial translation, and cause oxidative phosphorylation defects, which may be responsible for POI.
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http://dx.doi.org/10.1016/j.fertnstert.2019.05.005DOI Listing
September 2019

mutations cause high myopia.

J Med Genet 2019 10 12;56(10):671-677. Epub 2019 Jun 12.

Graduate School of Peking Union Medical College, Beijing, China

Background: High myopia (HM) is one of the leading causes of vision impairment worldwide, accompanied by a series of pathological ocular complications. Studies have shown that genetic factors play an important role in the pathogenesis of HM. The aim of our study is to identify a candidate gene for a large family with non-syndromic HM.

Methods: A large Chinese family, including 12 patients with non-syndromic HM, and 220 unrelated patients with HM, were recruited from the Department of Ophthalmology, Peking Union Medical College Hospital. Three affected subjects from the large family were selected to perform whole exome sequencing (WES). Rare heterozygous variants shared by all three subjects were retained and then Sanger sequencing was used to determine whether any of the remaining variants cosegregated with the disease phenotype. Furthermore, all coding regions of the candidate genes were analysed in 220 unrelated patients with HM. Immunofluorescence assay was used to detect the expression of the candidate gene in the eye. Annexin V/PI staining and flow cytometry were applied to detect cell apoptotic changes.

Results: WES identified a novel TNF receptor superfamily member 21 () variant, P146A, in a large Chinese family with HM, and another three rare heterozygous variants (P202L, E240* and A440G) in were found in 220 unrelated cases with HM. Immunofluorescence assay indicated that it is strongly expressed in the mouse eye. Compared with the wild type, the P146A variant could significantly increase adult retinal pigment epithelial cell line-19 cell apoptotic levels.

Conclusions: Variants in cause non-syndromic HM in Chinese population.
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http://dx.doi.org/10.1136/jmedgenet-2018-105684DOI Listing
October 2019

Carrying the T Allele of the SNP rs574344, an eQTL of GSTM1, Contributes to Longevity in the Han Chinese Population.

Genet Test Mol Biomarkers 2019 Jan 27;23(1):12-15. Epub 2018 Dec 27.

3 Department of Medical Genetics, Center for Genetics, National Research Institute of Family Planning , Beijing, China .

Background: There has been recent recognition that the GSTM1 gene is associated with successful aging and longevity. It has been hypothesized that individuals with a GSTM1 deletion are at a greater risk for developing a plethora of diseases. This study was carried out to investigate the association between the rs574344 single nucleotide polymorphism, an expression quantitative trait locus of GSTM1, and longevity in the Han Chinese population.

Materials And Methods: We performed a case-control study that comprised 526 long-lived subjects (>97 years of age) and 783 younger subjects (aged 19-80 years) from the general population who served as controls. Identification of the genotypes of rs574344 was accomplished by combining polymerase chain reaction with matrix-assisted laser desorption/ionization time-of-flight mass spectrometry.

Results: The long-lived study population, when compared with the controls, showed a significantly higher frequency of the T/T genotype and the T allele of rs574344. We determined that the T/T genotype is associated with a longer lifespan (OR = 5.972, 95% CI 1.798-19.833, p = 0.001, for all genders; p = 0.006 adjusted by gender). We also observed a significant difference (p < 0.05) in the distribution of alleles and genotypes in both the male group (TT vs. TA, OR = 1.043, 95% CI 1.022-1.067, p = 0.043) and the female group (TT vs. TA, OR = 3.592, 95% CI 0.982-13.147, p = 0.039) Conclusion: We found significant associations between both the T allele and the T/T genotype of rs574344 with longevity in the Han Chinese population.
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http://dx.doi.org/10.1089/gtmb.2018.0178DOI Listing
January 2019

Claudin-7 downregulation induces metastasis and invasion in colorectal cancer via the promotion of epithelial-mesenchymal transition.

Biochem Biophys Res Commun 2019 01 6;508(3):797-804. Epub 2018 Dec 6.

Department of Oncology, Beijing Shijitan Hospital, Capital Medical University, Beijing, 100038, China. Electronic address:

The dysregulation of the tight junctions (TJs) protein claudin-7 is closely related to the development and metastasis of colorectal cancer (CRC). The aim of this study was to investigate the expression of claudin-7 and characterize the relationship between claudin-7 expression and epithelial-mesenchymal transition (EMT) in CRC. In this study, the expression of claudin-7, E-cadherin, vimentin and snail-1 was detected by immunohistochemistry (IHC) in a set of 80 CRC specimens comprising 20 specimens each of well-differentiated, moderately differentiated, poorly differentiated and liver metastases tissues. The correlation between claudin-7 and EMT-related proteins in the stably transfected claudin-7 knockdown HCT116 cell line was analyzed by IHC, immunofluorescence (IF), Western blotting (WB) and nude mouse xenograft models. The results revealed that the expression of claudin-7 was downregulated as CRC tissue differentiation grade decreased, and that low claudin-7 expression corresponded to the downregulation of E-cadherin (r = 0.725, p < 0.001) and upregulation of vimentin (r = -0.376, p = 0.001) and snail-1 (r = -0.599, p < 0.001). Additionally, in the claudin-7 knockdown HCT116 cell line, the staining intensity and expression of E-cadherin was decreased, while the immunoreactivity and expression of vimentin and snail-1 was increased. Futhermore, the result of tumor formation experiment was consistent with CRC tissues. In conclusion, the expression of claudin-7 in CRC is downregulated as differentiation grade decreases. Claudin-7 downregulation may promote the invasion and metastasis of CRC by regulating EMT. Our results provide new perspectives for a potential therapeutic target for CRC.
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http://dx.doi.org/10.1016/j.bbrc.2018.10.049DOI Listing
January 2019

Mutations in EPAS1 in congenital heart disease in Tibetans.

Biosci Rep 2018 12 18;38(6). Epub 2018 Dec 18.

Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China

encodes HIF2 and is closely related to high altitude chronic hypoxia. Mutations in the coding sequence are associated with several kinds of human diseases, including syndromic congenital heart disease (CHD). However, whether there are rare coding variants related to Tibetan non-syndromic CHD have not been fully investigated. A group of 286 Tibetan patients with non-syndromic CHD and 250 unrelated Tibetan healthy controls were recruited from Qinghai, China. Sanger sequencing was performed to identify variations in the coding sequence. The novelty of identified variants was confirmed by the examination of 1000G and ExAC databases. Control samples were screened to establish that the rare candidate variants were specific to the Tibetan patients with non-syndromic CHD. Bioinformatics software was used to assess the conservation of the mutations and to predict their effects. The effect of mutations on the transcription of its target gene, , was assessed by dual-luciferase reporter assay. The mammalian two-hybrid assay was used to study the protein interactions between HIF2 and PHD2 or pVHL. We identified two novel mutations (NM_001430: c.607A>C, p.N203H; c.2170G>T, p.G724W) in two patients. The N203H mutation significantly affected the transcription activity of the promoter, especially in conditions of hypoxia. The N203H mutation also showed enhanced protein-protein interactions between HIF2 and PHD2, and HIF2 and pVHL, especially in conditions of hypoxia. However, the G724W mutation did not demonstrate the same effects. Our results indicate that EPAS1 mutations might have a potential causative effect on the development of Tibetan non-syndromic CHD.
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http://dx.doi.org/10.1042/BSR20181389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435565PMC
December 2018

CAPS Mutations Are Potentially Associated with Unexplained Recurrent Pregnancy Loss.

Am J Pathol 2019 01 17;189(1):124-131. Epub 2018 Oct 17.

Graduate School of Peking Union Medical College, Beijing, China; Center for Genetics, National Research Institute for Family Planning, Beijing, China.

Recurrent pregnancy loss (RPL) is a major concern for women's reproductive health. Several studies have proved that genetics is a major factor leading to unexplained RPL, but the maternal pathogenic genes involved in RPL remain largely unknown. A consanguineous family, including the parents who were cousins and their three daughters who had been diagnosed as having nonsyndromic unexplained RPL, was recruited in this study. A rare homozygous variant in calcyphosine (CAPS; ENST00000588776: c.377delC, p.Leu127Trpfs) might be the potential candidate variant for this RPL family through whole-exome sequencing. Sanger sequencing confirmed that the three affected sisters carried the homozygous p.Leu127Trpfs, whereas their parents carried the heterozygous p.Leu127Trpfs. CAPS encodes a Ca-binding protein and may play a role in the regulation of Ca transport. Although the precise underlying mechanisms remain unclear, the previous study suggested that they may be involved in cross talk between Ca signaling and cAMP-protein kinase A pathways, which are crucial to embryo implantation and pregnancy maintenance. Knockdown of CAPS expression might promote the expression of secreted phosphoprotein 1 and matrix metalloproteinase 9, and the release of prostaglandin E, which all played important roles in embryo implantation and early pregnancy maintenance. These results indicated that the autosomal recessive homozygous mutation, p.Leu127Trpfs, in CAPS might be a maternal effect causative mutation of RPL pathogenesis.
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http://dx.doi.org/10.1016/j.ajpath.2018.09.010DOI Listing
January 2019

Application of a deep convolutional neural network in the diagnosis of neonatal ocular fundus hemorrhage.

Biosci Rep 2018 12 7;38(6). Epub 2018 Dec 7.

Key Laboratory of Intelligent Information Processing, Advanced Computer Research Center, State Key Laboratory of Computer Architecture, Institute of Computing Technology, Chinese Academy of Sciences, Beijing 100190, China.

There is a disparity between the increasing application of digital retinal imaging to neonatal ocular screening and slowly growing number of pediatric ophthalmologists. Assistant tools that can automatically detect ocular disorders may be needed. In present study, we develop a deep convolutional neural network (DCNN) for automated classification and grading of retinal hemorrhage. We used 48,996 digital fundus images from 3770 newborns with retinal hemorrhage of different severity (grade 1, 2 and 3) and normal controls from a large cross-sectional investigation in China. The DCNN was trained for automated grading of retinal hemorrhage (multiclass classification problem: hemorrhage-free and grades 1, 2 and 3) and then validated for its performance level. The DCNN yielded an accuracy of 97.85 to 99.96%, and the area under the receiver operating characteristic curve was 0.989-1.000 in the binary classification of neonatal retinal hemorrhage (i.e., one classification vs. the others). The overall accuracy with regard to the multiclass classification problem was 97.44%. This is the first study to show that a DCNN can detect and grade neonatal retinal hemorrhage at high performance levels. Artificial intelligence will play more positive roles in ocular healthcare of newborns and children.
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http://dx.doi.org/10.1042/BSR20180497DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6435455PMC
December 2018

Consanguineous familial study revealed biallelic FIGLA mutation associated with premature ovarian insufficiency.

J Ovarian Res 2018 Jun 18;11(1):48. Epub 2018 Jun 18.

Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Meishan Road, Shushan, Hefei, 230022, China.

Background: To dissect the genetic alteration in two sisters with premature ovarian insufficiency (POI) from a consanguineous family.

Methods: Whole-exome sequencing technology was used in the POI proband, bioinformatics analysis was carried out to identify the potential genetic cause in this pedigree. Sanger sequencing analyses were performed to validate the segregation of the variant within the pedigree. In silico analysis was also used to predict the effect and pathogenicity of the variant.

Results: Whole-exome sequencing analysis identified novel and rare homozygous mutation associated with POI, namely mutation in FIGLA (c.2 T > C, start codon shift). This homozygous mutation was also harbored by the proband's sister with POI and was segregated within the consanguineous pedigree. The mutation in the start codon of the FIGLA gene alters the open reading frame, leading to a FIGLA knock-out like phenotype.

Conclusions: Biallelic mutations in FIGLA may be the cause of POI. This study will aid researchers and clinicians in genetic counseling of POI and provides new insights into understanding the mode of genetic inheritance of FIGLA mutations in POI pathology.
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http://dx.doi.org/10.1186/s13048-018-0413-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6006558PMC
June 2018

Identification of LBX2 as a novel causal gene of atrial septal defect.

Int J Cardiol 2018 Aug 11;265:188-194. Epub 2018 Apr 11.

Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China. Electronic address:

Background: Atrial septal defect (ASD) is one of the most common cardiac malformations worldwide. Several genes have been identified so far, which can merely explain small proportion of all the cases, therefore, it is anticipated that there are additional genes causing ASD. The aims of this study were to identify the causal gene of ostium secundum atrial septal defect (ASDII) in a Chinese family.

Methods: Whole exome sequencing was performed in three affected members and one control in the ASDII family. We screened mutations of LBX2 in 300 unrelated ASD patients and validated in 400 normal controls by Sanger sequencing. LBX2 knockout zebrafish was generated by CRISPR/Cas9 to detect whether lbx2 deficiency influenced cardiac development.

Results: A rare missense mutation in LBX2 (c.A403G: p.K135E) was identified as the pathogenic cause of ASD. Subsequent mutation screening revealed two missense variants in 3 of 300 sporadic patients. We observed expanded size of atrium and ventricle in LBX2 knockout zebrafish through hematoxylin-eosin staining, more incompact distribution of cardiac myocytes was also discovered in homozygote compared with in wildtype. Furthermore, we performed in situ hybridization of crip2 gene to trace the cardiac neural crest cells in the embryo stage and found that the migration of neural crest cells was obviously delayed in the homozygotes.

Conclusions: We identified LBX2 for the first time as a pathogenic gene of ASDII. LBX2 deficiency may cause abnormal development of heart through influencing the migration of neural crest cells and affect the process of cardiac septation.
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http://dx.doi.org/10.1016/j.ijcard.2018.04.038DOI Listing
August 2018

Retrospective investigation of retinoblastoma in Chinese patients.

Oncotarget 2017 Dec 23;8(65):108492-108497. Epub 2017 May 23.

Center for Genetics, National Research Institute for Family Planning, Beijing, China.

This is a retrospective investigation of patients with Retinoblastoma (RB) conducted from 2013 to 2016 at the Quanzhou Maternal and Child Health Hospital (China). Demographic and clinical characteristics, treatment outcomes, and risk factors were studied. In total, 436 patients were included in the study. Most of the findings obtained in this study are consistent with other previous reports. The male: female ratio was 1.41:1, and the unilateral: bilateral ratio was 1.51:1. Leukocoria was the most common presenting sign (79.44%), followed by strabismus (12.38%). While, the overall rates of enucleation (15.82%) and mortality (0.92%) were markedly lower than in other reports of RB in Chinese, and most of the patients received conservative therapy. There were signficant differences ( < 0.001) in the age of at first sign and diagnosis, and treatment modalities between patients with bilateral and unilateral RB. The treatment modalities did not show a specific trend over the 3-year study period. Our results suggest that an incorrect initial diagnosis and long lag time may be risk factors for ineffective treatment and a poor prognosis in patients with RB. This was a comprehensive retrospective investigation in which the sample size exceeded most previous retrospective investigations of RB. Our study confirmed that early detection, accurate diagnosis, and active intervention are conducive to control of retention of patients' vision. Fundus examinations, education regarding the early signs of RB, and optimization of the therapeutic strategy of RB may play important roles in ocular health.
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http://dx.doi.org/10.18632/oncotarget.18174DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5752458PMC
December 2017

A novel homozygous mutation of bone morphogenetic protein 15 identified in a consanguineous marriage family with primary ovarian insufficiency.

Reprod Biomed Online 2018 Feb 26;36(2):206-209. Epub 2017 Oct 26.

Graduate School of Peking Union Medical College, Beijing 100730, China; Center for Genetics, National Research Institute for Family Planning, Beijing 100081, China. Electronic address:

The aim of this study was to explore the pathogenic gene in a primary ovarian insufficiency (POI) patient from a consanguineous marriage family. The proband and her healthy mother were selected for whole-exome sequencing. By applying a strict filtering strategy, we found a novel homozygous missense mutation, c.G1070A (p.C357Y), of BMP15 in the proband, whereas her mother was heterozygous for this mutation. The mutation was highly conserved among species and predicted to be disorder causing. This study has revealed a novel homozygous mutation of the BMP15 gene that may be associated with POI.
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http://dx.doi.org/10.1016/j.rbmo.2017.10.104DOI Listing
February 2018

Sequence variants of KHDRBS1 as high penetrance susceptibility risks for primary ovarian insufficiency by mis-regulating mRNA alternative splicing.

Hum Reprod 2017 10;32(10):2138-2146

Department of Obstetrics and Gynecology, Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Meishan Road, Shushan, Hefei 230022, China.

Study Question: Does a novel heterozygous KHDRBS1 variant, identified using whole-exome sequencing (WES) in two patients with primary ovarian insufficiency (POI) in a pedigree, cause defects in mRNA alternative splicing?

Summary Answer: The heterozygous variant of KHDRBS1 was confirmed to cause defects in alternative splicing of many genes involved in DNA replication and repair.

What Is Known Already: Studies in mice revealed that Khdrbs1 deficient females are subfertile, which manifests as delayed sexual maturity and significantly reduced numbers of secondary and pre-antral follicles. No mutation of KHDRBS1, however, has been reported in patients with POI.

Study Design Size, Duration: This genetic and functional study used WES to find putative mutations in a POI pedigree. Altogether, 215 idiopathic POI patients and 400 healthy controls were screened for KHDRBS1 mutations.

Participants/materials, Setting, Methods: Two POI patients were subjected to WES to identify sequence variants. Mutational analysis of the KHDRBS1 gene in 215 idiopathic POI patients and 400 healthy controls were performed. RNA-sequencing was carried out to find the mis-regulation of gene expression due to KHDRBS1 mutation. Bioinformatics was used to analyze the change in alternative splicing events.

Main Results And The Role Of Chance: We identified a heterozygous mutation (c.460A > G, p.M154V) in KHDRBS1 in two patients. Further mutational analysis of 215 idiopathic POI patients with the KHDRBS1 gene found one heterozygous mutation (c.263C > T, p.P88L). We failed to find these two mutations in 400 healthy control women. Using RNA-sequencing, we found that the KGN cells expressing the M154V KHDRBS1 mutant had different expression of 66 genes compared with wild-type (WT) cells. Furthermore, 145 genes were alternatively spliced in M154V cells, and these genes were enriched for DNA replication and repair function, revealing a potential underlying mechanism of the pathology that leads to POI.

Limitations Reasons For Caution: Although the in vitro assays demonstrated the effect of the KHDRBS1 variant on alternative splicing, further studies are needed to validate the in vivo effects on germ cell and follicle development.

Wider Implications Of The Findings: This finding provides researchers and clinicians a better understanding of the etiology and molecular mechanism of POI.

Study Funding/competing Interest(s): This study was supported by the Ministry of Science and Technology of China (2012CB944704; 2012CB966702), National Research Institute for Family Planning (2017GJZ05), the National Natural Science Foundation of China (31171429) and Beijing Advanced Innovation Center for Structural Biology. The authors declare no conflict of interest.
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http://dx.doi.org/10.1093/humrep/dex263DOI Listing
October 2017

Exome Sequencing and Gene Prioritization Correct Misdiagnosis in a Chinese Kindred with Familial Amyloid Polyneuropathy.

Sci Rep 2016 05 23;6:26362. Epub 2016 May 23.

National Research Institute of Family Planning, Beijing, China.

Inherited neuropathies show considerable heterogeneity in clinical manifestations and genetic etiologies, and are therefore often difficult to diagnose. Whole-exome sequencing (WES) has been widely adopted to make definite diagnosis of unclear conditions, with proven efficacy in optimizing patients' management. In this study, a large Chinese kindred segregating autosomal dominant polyneuropathy with incomplete penetrance was ascertained through a patient who was initially diagnosed as Charcot-Marie-Tooth disease. To investigate the genetic cause, forty-six living family members were genotyped by SNP microarrays, and one confirmed patient was subject to WES. Through systematic computational prioritization, we identified a missense mutation c.G148T in TTR gene which results in a p.V50L substitution known to cause transthyretin-related familial amyloid polyneuropathy. Co-segregation analysis and clinical follow-up confirmed the new diagnosis, which suggested new therapeutic options to the patients and informed high risk family members. This study confirms WES as a powerful tool in translational medicine, and further demostrates the practical utility of gene prioritization in narrowing the scope of causative mutation.
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http://dx.doi.org/10.1038/srep26362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4876459PMC
May 2016

Claudin-7 indirectly regulates the integrin/FAK signaling pathway in human colon cancer tissue.

J Hum Genet 2016 Aug 28;61(8):711-20. Epub 2016 Apr 28.

Department of Biochemistry and Molecular Biology, Capital Medical University, Beijing, China.

The claudin family of proteins is integral to the structure and function of tight junctions. The role of claudin-7 (Cldn-7, CLDN7) in regulating the integrin/focal adhesion kinase (FAK)/ERK signaling pathway remains poorly understood. Therefore, we investigated differences in gene expression, primarily focusing on CLDN7 and integrin/FAK/ERK signaling pathway genes, between colon cancer and adjacent normal tissues. Quantitative real-time reverse transcription-PCR and immunohistochemistry were utilized to verify the results of mRNA and protein expression, respectively. In silico analysis was used to predict co-regulation between Cldn-7 and integrin/FAK/ERK signaling pathway components, and the STRING database was used to analyze protein-protein interaction pairs among these proteins. Meta-analysis of expression microarrays in The Cancer Genome Atlas (TCGA) database was used to identify significant correlations between Cldn-7 and components of predicted genes in the integrin/FAK/ERK signaling pathway. Our results showed marked cancer stage-specific decreases in the protein expression of Cldn-7, Gelsolin, MAPK1 and MAPK3 in colon cancer samples, and the observed changes for all proteins except Cldn-7 were in agreement with changes in the corresponding mRNA levels. Cldn-7 might indirectly regulate MAPK3 via KRT8 due to KRT8 co-expression with MAPK3 or CLDN7. Our bioinformatics methods supported the hypothesis that Cldn-7 does not directly regulate any genes in the integrin/FAK/ERK signaling pathway. These factors may participate in a common network that regulates cancer progression in which the MAPK pathway serves as the central node.
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http://dx.doi.org/10.1038/jhg.2016.35DOI Listing
August 2016

Difference in left renal vein pressure: an indicator for free of reconstruction after ligation in retroperitoneal tumor patients.

Sci Rep 2015 Dec 11;5:18126. Epub 2015 Dec 11.

Department of Retroperitoneal Tumors Surgery Peking University International Hospital, Beijing, P.R. China.

We hypothesized that the left renal vein pressure difference (ΔP) before and after the ligation can serve as an objective indicator for free of reconstruction after resection of a retroperitoneal tumor with renal segment of inferior vena cava and right kidney. After established a model of left renal vein compression, 45 miniature pigs were operated on experimental procedures including renal segment of inferior vena cava resection, right nephrectomy, and left renal vein ligation. The ΔPs of left renal vein before and after the ligation were measured. Safe ΔP variation without causing acute kidney injury was calculated using regression analysis. In human the safety range of ΔP before and after ligation of the left renal vein was calculated by diuretic response test. The safety range of ΔP in animals or human was 0-11.9 or 0-17.5 cm H2O, respectively. The renal function changed dramatically (p < 0.01), characterized by a significant increase in the rate of acute kidney injury when the ΔP was beyond the upper limit of the safety range. In conclusion, ΔP can predict free of reconstruction after resection of a retroperitoneal tumor with the renal segment of the inferior vena cava and the right kidney.
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http://dx.doi.org/10.1038/srep18126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4676037PMC
December 2015

A novel variation of GDF3 in Chinese Han children with a broad phenotypic spectrum of non-syndromic CHDs.

Cardiol Young 2015 Oct 5;25(7):1263-7. Epub 2014 Nov 5.

3Center for Genetics,National Research Institute for Family Planning,Beijing,China.

Background: The GDF3 gene plays a fundamental role in embryonic morphogenesis. Recent studies have indicated that GDF3 plays a previously unrecognised role in cardiovascular system development. Non-syndromic CHDs might be a clinically isolated manifestation of GDF3 mutations. The purpose of the present study was to identify potential pathological mutations in the GDF3 gene in Chinese children with non-syndromic CHDs, and to gain insight into the aetiology of non-syndromic CHDs.

Methods: A total of 200 non-syndromic CHDs patients and 202 normal control patients were sampled. There were two exons of the human GDF3 gene amplified using polymerase chain reaction. The polymerase chain reaction products were purified and directly sequenced.

Results: One missense mutation (c.C635T, p.Ser212 Leu, phenotype: isolated muscular ventricular septal defect) was found that has not been reported previously.

Conclusions: To the best of our knowledge, this is the first study to investigate the role of the GDF3 gene in non-syndromic CHDs. Our results expand the spectrum of mutations associated with CHDs and first suggest the potentially disease-related GDF3 gene variant in the pathogenesis of CHDs.
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http://dx.doi.org/10.1017/S1047951114002170DOI Listing
October 2015