Publications by authors named "Zhengjun Jia"

25 Publications

  • Page 1 of 1

Prenatal case of Simpson-Golabi-Behmel syndrome with a de novo 370Kb-sized microdeletion of Xq26.2 compassing partial GPC3 gene and review.

Mol Genet Genomic Med 2021 Aug 22;9(8):e1750. Epub 2021 Jul 22.

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

Background: Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is a rare X-linked recessive disorder characterized by pre- and postnatal overgrowth and a broad spectrum of anomalies including craniofacial dysmorphism, heart defects, renal, and genital anomalies. Due to the ultrasound findings are not pathognomonic for this syndrome, most clinical diagnosis of SGBS1 are made postnatally.

Methods: A pregnant woman with abnormal prenatal sonographic findings was advised to perform molecular diagnosis. Single nucleotide polymorphism array (SNP array) was performed in the fetus, and the result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR).

Results: The prenatal sonographic presented with increased nuchal translucency at 13 gestational weeks, and later at 21 weeks with cleft lip and palate, heart defect, increased amniotic fluid index and over growth. A de novo 370Kb-deletion covering the 5'-UTR and exon 1 of GPC3 gene was detected in the fetus by SNP array, which was subsequently confirmed by MLPA and qPCR.

Conclusion: The de novo 370Kb hemizygous deletion of 5'-UTR and exon 1 of GPC3 results in the SGBS1 of this Chinese family. Combination of ultrasound and genetics tests helped us effectively to diagnose the prenatal cases of SGBS1. Our findings also enlarge the spectrum of mutations in GPC3 gene.
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http://dx.doi.org/10.1002/mgg3.1750DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8404223PMC
August 2021

Clinical significance of S100B protein in pregnant woman with early- onset severe preeclampsia.

Ginekol Pol 2021 Jun 9. Epub 2021 Jun 9.

Department of Obstetrics, Maternal and child health hospital of Hunan Province Changsha, Hunan, China.

Objectives: Preeclampsia is one of the most feared complications of pregnancy, which can progress rapidly to serious complications such as death of both mother and fetus. To present, the leading cause of preeclampsia is still debated. The purpose of this article was to explore the clinical significance of S100B protein, a kind of Ca2+ -sensor protein, in the early-onset severe preeclampsia.

Material And Methods: Nine pregnant women with early-onset severe preeclampsia (the study group) and 13 healthy pregnant women (the control group) were included in this study. The level of S100B in the amniotic fluid, maternal blood, and umbilical cord blood were detected by enzyme-linked immunosorbent assay (ELISA) and surface plasmon resonance imaging (SPRi) methods. Diagnostic values of S100B for early-onset severe preeclampsia were assessed by Receiver Operating Characteristic (ROC) curve analysis.

Results: The levels of S100B in maternal blood and amniotic fluid in the study group were higher than those in the control group (p < 0.05). ROC curve analysis showed that S100B detected by SPRi method (SPRi-S100B) showed a cut-off level of 181 ng/mL with sensitivity of 100%, a specificity of 84.6%, and a Youden index of 0.846 in the maternal blood, which had better clinical significance and diagnostic value (at than that detected by ELISA (ELISA-S100B).

Conclusions: The levels of S100B detected by SPRi in maternal blood can indicate early-onset severe preeclampsia and perinatal brain injury.
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http://dx.doi.org/10.5603/GP.a2021.0126DOI Listing
June 2021

Clinical and genetic analysis of classical Ehlers-Danlos syndrome patient caused by synonymous mutation in COL5A2.

Mol Genet Genomic Med 2021 May 8;9(5):e1632. Epub 2021 Apr 8.

Reproductive and Genetic Hospital of CITIC-Xiangya, Changsha, PR China.

Background: Classical Ehlers-Danlos syndrome (cEDS) is a heterogeneous connective tissue disorder that mainly results from the germline mutation of COL5A1 and COL5A2. The majority of the COL5A2 mutations reported to date represent structural mutations, including missense or in-frame exon-skipping splice mutations. The only reported synonymous mutation was expected to affect on splicing of exon 29 by prediction programs which should be further confirmed.

Methods: Whole exome sequencing was performed to identify the genetic variants of a Chinese boy who was characterized by skin hyperextensibility, abnormal scarring, hypermobile joints and scoliosis. Sanger sequencing was used to validate the variants in his parents. Reverse transcription polymerase chain reaction (RT-PCR) was performed to analyze the functional effects of the variant.

Results: A de novo heterozygous synonymous variant (NM_000393.5:c.1977 G>A) of COL5A2 gene was identified in the patient. The results of RT-PCR revealed that the synonymous variant led to skipping of exon 29 in the RNA transcript.

Conclusions: Our study supplies further supporting evidence that the synonymous COL5A2 mutation c.1977 G>A can cause skipping of exon 29 in the RNA transcript, thus resulting in the production of mutant α2(V)-chains and clinical phenotype of cEDS. This result highlights the need to include splicing-altering synonymous mutations into the screening for cEDS.
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http://dx.doi.org/10.1002/mgg3.1632DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8172199PMC
May 2021

Integrated CNV-seq, karyotyping and SNP-array analyses for effective prenatal diagnosis of chromosomal mosaicism.

BMC Med Genomics 2021 02 25;14(1):56. Epub 2021 Feb 25.

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, Hunan, China.

Background: Emerging studies suggest that low-coverage massively parallel copy number variation sequencing (CNV-seq) more sensitive than chromosomal microarray analysis (CMA) for detecting low-level mosaicism. However, a retrospective back-to-back comparison evaluating accuracy, efficacy, and incremental yield of CNV-seq compared with CMA is warranted.

Methods: A total of 72 mosaicism cases identified by karyotyping or CMA were recruited to the study. There were 67 mosaic samples co-analysed by CMA and CNV-seq, comprising 40 with sex chromosome aneuploidy, 22 with autosomal aneuploidy and 5 with large cryptic genomic rearrangements.

Results: Of the 67 positive mosaic cases, the levels of mosaicism defined by CNV-seq ranged from 6 to 92% compared to the ratio from 3 to 90% by karyotyping and 20% to 72% by CMA. CNV-seq not only identified all 43 chromosomal aneuploidies or large cryptic genomic rearrangements detected by CMA, but also provided a 34.88% (15/43) increased yield compared with CMA. The improved yield of mosaicism detection by CNV-seq was largely due to the ability to detect low level mosaicism below 20%.

Conclusion: In the context of prenatal diagnosis, CNV-seq identified additional and clinically significant mosaicism with enhanced resolution and increased sensitivity. This study provides strong evidence for applying CNV-seq as an alternative to CMA for detection of aneuploidy and mosaic variants.
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http://dx.doi.org/10.1186/s12920-021-00899-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7905897PMC
February 2021

Whole genome sequencing reveals translocation breakpoints disrupting TP63 gene underlying split hand/foot malformation in a Chinese family.

Mol Genet Genomic Med 2021 03 20;9(3):e1604. Epub 2021 Jan 20.

Department of Medical Genetics, National Health Commission Key Laboratory of Birth Defects Research, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, China.

Background: Split hand/foot malformation (SHFM) is a congenital limb developmental disorder, which impairs the fine activities of hand/foot in the affected individuals seriously. SHFM is commonly inherited as an autosomal dominant disease with incomplete penetrance. Chromosomal aberrations such as copy number variations and translocations have been linked to SHFM. This study aimed to identify the genetic cause for three patients with bilateral hand and foot malformation in a Chinese family.

Methods: Karyotyping, single-nucleotide polymorphism (SNP) array, whole exome sequencing, whole genome sequencing, and Sanger sequencing were applied to identify the pathogenic variant.

Results: Karyotyping revealed that the three patients had balanced reciprocal translocation, 46, XX, t(3;15) (q29;q22). SNP array identified no pathogenic copy number variation in the proband. Trio-WES (fetus-mother-father) sequencing results revealed no pathogenic variants in the genes related to SHFM. Whole-genome low-coverage mate-pair sequencing (WGL-MPS), breakpoint PCR, and Sanger sequencing identified the breakpoints disrupting TP63 in the patients, but not in healthy family members.

Conclusion: This study firstly reports that a translocation breakpoint disrupting TP63 contributes to the SHFM in a Chinese family, which expands our knowledge of genetic risk and counseling underlying SHFM. It provides a basis for genetic counseling and prenatal diagnosis (preimplantation genetic diagnosis) for this family.
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http://dx.doi.org/10.1002/mgg3.1604DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8104154PMC
March 2021

[Genetic analysis of a pedigree with MECP duplication syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Oct;37(10):1146-1149

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.

Objective: To explore the genetic etiology of a pedigree with mental retardation and hypotonia by using chromosome microarray analysis (CMA), low coverage massive parallel copy number variation sequencing (CNV-seq) and quantitative PCR (qPCR).

Methods: Genomic DNA was extracted from peripheral blood samples from two male patients and healthy members from the pedigree. CNV-seq was carried out for one patient. Suspected CNV was verified by qPCR. CNV-seq or single nucleotide polymorphism array (SNP array) were carried out for another patient and his family members.

Results: Both patients showed severe hypotonia and global development delay, in particular language delay. CNV-seq and SNP array indicated that both patients had carried a Xq28 duplication, with spanned 0.26 Mb and 0.42 Mb, respectively. Both duplications encompassed the MECP2 gene. CNV-seq analysis of their family members confirmed that the mother and one sister had carried similar duplications, while an elder brother was normal.

Conclusion: CNV-seq and CMA are rapid and effective tools for the diagnosis of MECP2 duplication syndrome in children with mental retardation, hypotonia and recurrent infections.
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http://dx.doi.org/10.3760/cma.j.cn511374-20191014-00525DOI Listing
October 2020

[Non-invasive prenatal testing and genetic analysis of a fetus with partial trisomy 21].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Oct;37(10):1079-1083

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.

Objective: To carry out prenatal diagnosis for a fetus with high risk predicted by non-invasive prenatal testing (NIPT).

Methods: Next-generation sequencing (NGS) was used to analyze free fetal DNA (ffDNA) in the maternal plasma. Chromosomal karyotyping and single nucleotide polymorphism array (SNP-array) were used to ascertain copy number variation in the fetus and its parents.

Results: SNP-array analysis and chromosomal karyotyping revealed that the fetus had a 15.018 Mb duplication at 4q34.1q35.2 and a 7.678 Mb duplication at 21q11.2q21.1, which were derived from a t(4;21)(q34.1;q21.1) translocation carried by its mother.

Conclusion: NIPT is capable of detecting submicroscopic chromosomal abnormalities of the fetus. Combined use of genetic techniques, in particular SNP-array, is crucial for the diagnosis of partial trisomy 21q in this case.
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http://dx.doi.org/10.3760/cma.j.cn511374-20191121-00601DOI Listing
October 2020

[Xq;Yq translocation in a patient with premature ovarian insufficiency].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2020 Sep;37(9):942-945

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.

Objective: To explore the genetic basis for a patient with premature ovarian insufficiency.

Methods: Chromosomal G-banding and C-banding, single nucleotide polymorphism array (SNP-array), fluorescence in situ hybridization (FISH) and Y chromosome microdeletion assay were used for the analysis.

Results: With the combined techniques, the patient was found to carry a Xq;Yq translocation, with a karyotype of 46,X,der(X)t(X;Y)(q25;q12).ish der(X)(Tel XYp+,Tel XYq+,Yq12+).

Conclusion: Unbalanced Xq;Yq translocation probably underlay the premature ovarian insufficiency in this patient.
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http://dx.doi.org/10.3760/cma.j.cn511374-20191001-00505DOI Listing
September 2020

Identification of a novel gross deletion of TCOF1 in a Chinese prenatal case with Treacher Collins syndrome.

Mol Genet Genomic Med 2020 08 15;8(8):e1313. Epub 2020 Jun 15.

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

Background: Treacher Collins syndrome (TCS) is the most common mandibulofacial dysostosis with an autosomal dominant or rarely recessive manner of inheritance. It is still challenging to make a definite diagnosis for affected fetuses with TCS only depending on the ultrasound screening. Genetic tests can contribute to the accurate diagnosis for those prenatal cases.

Methods: Targeted exome sequencing was performed in a fetus of a Chinese family, who presenting an abnormal facial appearance by prenatal 2D and 3D ultrasound screening, including micrognathia, nasal bridge pit, and abnormal auricle. The result was validated with multiplex ligation-dependent probe amplification (MLPA) and real-time quantitative PCR (qPCR).

Results: A novel 2-6 exons deletion of TCOF1 gene was identified and confirmed by the MLPA and qPCR in the fetus, which was inherited from the affected father with similar facial anomalies.

Conclusion: The heterozygous deletion of 2-6 exons in TCOF1 results in the TCS of this Chinese family. Our findings not only enlarge the spectrum of mutations in TCOF1 gene, but also highlight the values of combination of ultrasound and genetics tests in diagnosis of craniofacial malformation-related diseases during perinatal period.
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http://dx.doi.org/10.1002/mgg3.1313DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434750PMC
August 2020

Clinical and molecular characterization of 12 prenatal cases of Cri-du-chat syndrome.

Mol Genet Genomic Med 2020 08 4;8(8):e1312. Epub 2020 Jun 4.

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

Background: This study aimed to define the molecular basis for 12 prenatal cases of Cri-du-chat syndrome (CdCS) and the potential genotyping-phenotyping association.

Methods: Karyotyping and single nucleotide polymorphism array analyses for copy number variants were performed.

Results: Nine cases had 5p terminal deletions and three had 5p interstitial deletions, and these cases had variable deletion sizes with partial overlapping. Phenotypically, besides intrauterine growth restriction (IUGR) and brain as well as heart abnormalities, hypospadias, and lung dysplasia were observed. Potential genetic causes for specific phenotypes in these cases were identified.

Conclusion: This study defined the molecular bases for the patients of CdCS, which is important for genetic counseling for these families. The findings of present study expand the clinical features of CdCS in the fetal period, and provided important information for further refining the genotypic-phenotypic correlations for this syndrome.
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http://dx.doi.org/10.1002/mgg3.1312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7434726PMC
August 2020

Variants in CAPZA2, a member of an F-actin capping complex, cause intellectual disability and developmental delay.

Hum Mol Genet 2020 06;29(9):1537-1546

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.

The actin cytoskeleton is regulated by many proteins including capping proteins that stabilize actin filaments (F-actin) by inhibiting actin polymerization and depolymerization. Here, we report two pediatric probands who carry damaging heterozygous de novo mutations in CAPZA2 (HGNC: 1490) and exhibit neurological symptoms with shared phenotypes including global motor development delay, speech delay, intellectual disability, hypotonia and a history of seizures. CAPZA2 encodes a subunit of an F-actin-capping protein complex (CapZ). CapZ is an obligate heterodimer consisting of α and β heterodimer conserved from yeast to human. Vertebrate genomes contain three α subunits encoded by three different genes and CAPZA2 encodes the α2 subunit. The single orthologue of CAPZA genes in Drosophila is cpa. Loss of cpa leads to lethality in early development and expression of the human reference; CAPZA2 rescues this lethality. However, the two CAPZA2 variants identified in the probands rescue this lethality at lower efficiency than the reference. Moreover, expression of the CAPZA2 variants affects bristle morphogenesis, a process that requires extensive actin polymerization and bundling during development. Taken together, our findings suggest that variants in CAPZA2 lead to a non-syndromic neurodevelopmental disorder in children.
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http://dx.doi.org/10.1093/hmg/ddaa078DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7268783PMC
June 2020

Prenatal genetic analysis and differential pregnancy outcomes of two de novo cases showing mosaic isodicentric Y chromosome.

Mol Cytogenet 2020 11;13. Epub 2020 Feb 11.

The prenatal diagnosis center of Hunan Province, The Maternal and Child Health Hospital of Hunan Province, 53 Xiangchun Road, Kaifu District, Changsha City, Hunan Province China.

Background: Fetal cells collected from the amniotic fluid of two pregnant women indicated sex chromosome abnormalities. Therefore, we performed G-banded chromosome karyotype analysis, single nucleotide polymorphism array (SNP array), fluorescence in situ hybridization (FISH), and sequence-tagged sites (STS) analysis of the Y chromosome to determine the rare molecular genetics of the two fetuses.

Case Presentation: The karyotypes of the fetuses from patients 1 and 2 were mos 45,X[92]/46,X,+idic(Y)(q11.21)[8] and mos 45,X[20]/46,X,+idic(Y)(q11.223)[80], respectively. Fetus 1 had a 7.76 Mb deletion in Yq11.222q11.23 and a 15.68 Mb duplication in Yp11.2q11.21. Fetus 2 had 21 Mb of repetitive segments in Yp11.3q11.223. Azoospermia factor (AZF) detection by STS analysis revealed a missing AZFb+c region in fetus 1 and three functional AZF regions in fetus 2. The isodicentric Y chromosome (idic (Y)) in both fetuses arose de novo. The pregnancy of patient 1 was terminated, whereas the fetus of patient 2 was delivered and is now 10 months old with normal appearance and growth.

Conclusion: A combination of technologies such as chromosome karyotyping, FISH, SNP arrays, and STS analysis of the Y chromosome is important in prenatal diagnosis to reduce birth defect rates and improve the health of the Chinese population.
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http://dx.doi.org/10.1186/s13039-020-0472-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014639PMC
February 2020

The Epilepsy of Infancy With Migrating Focal Seizures: Identification of Mutations of the Gene That Exert Inhibitory Effects on the Corresponding Heteromeric K1.1/K1.2 Potassium Channel.

Front Cell Neurosci 2020 24;14. Epub 2020 Jan 24.

INSERM, Aix-Marseille University, INMED, UMR1249, Marseille, France.

The epilepsy of infancy with migrating focal seizures (EIMFS; previously called Malignant migrating partial seizures of infancy) are early-onset epileptic encephalopathies (EOEE) that associate multifocal ictal discharges and profound psychomotor retardation. EIMFS have a genetic origin and are mostly caused by mutations in the gene, and much more rarely in the gene. and respectively encode the K1.1 (Slack) and K1.2 (Slick) subunits of the sodium-dependent voltage-gated potassium channel K. Functional analyses of the corresponding mutant homomeric channels suggested gain-of-function effects. Here, we report two novel, truncating mutations of : one mutation is frameshift (p.L48Qfs43), is situated in the N-terminal domain, and was found in a patient with EOEE (possibly EIMFS); the other mutation is nonsense (p.K564*), is located in the C-terminal region, and was found in a typical EIMFS patient. Using whole-cell patch-clamp recordings, we have analyzed the functional consequences of those two novel mutations on reconstituted K1.2 homomeric and K1.1/K1.2 heteromeric channels in transfected chinese hamster ovary (CHO) cells. We report that both mutations significantly impacted on K function; notably, they decreased the global current density of heteromeric channels by ~25% (p.K564*) and ~55% (p.L48Qfs43). Overall our data emphasize the involvement of in EOEE and provide novel insights into the role of heteromeric K channel in the severe -related epileptic phenotypes. This may have important implications regarding the elaboration of future treatment.
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http://dx.doi.org/10.3389/fncel.2020.00001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6992647PMC
January 2020

Analysis of balanced reciprocal translocations in patients with subfertility using single-molecule optical mapping.

J Assist Reprod Genet 2020 Mar 5;37(3):509-516. Epub 2020 Feb 5.

Department of Obstetrics and Gynecology, PLA General Hospital, Beijing, 100853, China.

Purpose: Approximately 1% of individuals who carry a balanced reciprocal translocation (BRT) are subfertile. Current karyotyping does not have the resolution to determine whether the breakpoints of the involved chromosomes perturb genes important for fertility. The aim of this study was to apply single-molecule optical mapping (SMOM) to patients presenting for IVF (in vitro fertilization) to ascertain whether the BRT disrupted any genes associated with normal fertility.

Methods: Nine subfertile patients with different BRTs were recruited for the study. Methyltransferase enzyme DLE1 was used to fluorescently label their genomic DNA samples at the recognition motif CTTAAG. The SMOM was performed on the Bionano platform, and long molecules aligned against the reference genome hg19 to identify the breakpoint regions. Mate-pair and PCR-Sanger sequencing were used to confirm the precise breakpoint sequences.

Results: Both breakpoint regions in each of the nine BRTs were finely mapped to small regions of approximately 10 Kb, and their positions were consistent with original cytogenetic banding patterns determined by karyotyping. In three BRTs, breakpoints disrupted genes known to be associated with male infertility, namely NUP155 and FNDC3A [46,XY,t(5;13)(p15;q22)], DPY19L1 [46,XY,t(1;7)(p36.3;p15), and BAI3 [46,XY,t(3;6)(p21;q16)].

Conclusions: The SMOM has potential clinical application as a rapid tool to screen patients with BRTs for underlying genetic causes of infertility and other diseases.
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http://dx.doi.org/10.1007/s10815-020-01702-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7125258PMC
March 2020

[Genetic analysis of a child with mental retardation and hypospadia].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Dec;36(12):1199-1202

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan 410008, China.

Objective: To carry out genetic testing for a boy presenting with mental retardation and hypoplasia.

Methods: Conventional karyotyping, fluorescence in situ hybridization (FISH) and single nucleotide polymorphism based array (SNP-array) were used to analyze the boy and his parents.

Results: SNP-array has detected a 25.7 Mb microduplication at 2q33.3q36.3 in the boy. Chromosomal karyotyping and FISH analysis indicated that his mother had a karyotype of 46,XX,ish ins(11;2) (p15;q33q36), and that the boy has carried an abnormal chromosome 11 derived from the maternal translocation. The karyotype of the boy was ascertained as 46,XY,ish der(11)ins(11;2) (p15;q33q36)mat.

Conclusion: SNP-array combined with G-banding and FISH can delineate the cryptic translocation and is valuable for the assessment of recurrence risk for subsequent pregnancies.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.12.012DOI Listing
December 2019

A De Novo Variant Identified in the PPP2R1A Gene in an Infant Induces Neurodevelopmental Abnormalities.

Neurosci Bull 2020 Feb 17;36(2):179-182. Epub 2019 Sep 17.

National Health Commission Key Laboratory of Birth Defects Research, Prevention and Treatment, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, 410008, China.

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http://dx.doi.org/10.1007/s12264-019-00430-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6977796PMC
February 2020

The first case of a non-infertile female patient with Pitt-Hopkins syndrome.

Am J Med Genet A 2019 11 28;179(11):2311-2314. Epub 2019 Aug 28.

Department of Medical Genetics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

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http://dx.doi.org/10.1002/ajmg.a.61325DOI Listing
November 2019

Molecular investigation in Chinese patients with primary carnitine deficiency.

Mol Genet Genomic Med 2019 09 30;7(9):e901. Epub 2019 Jul 30.

Hunan Provincial Maternal and Child Health Care Hospital, Changsha, Hunan, China.

Background: Primary carnitine deficiency (PCD) is an autosomal recessive disorder of carnitine transportation caused by mutations in the SLC22A5 that lead to low serum carnitine levels and decreased intracellular carnitine accumulation. Characteristic clinical findings are hypoketotic hypoglycemia and skeletal and cardiac myopathy.

Objective: To genetically diagnose 24 unrelated Chinese patients with PCD, including 18 infants and six adults.

Methods: The entire coding region and the intron-exon boundaries of SLC22A5 were amplified by polymerase chain reaction (PCR). In silico analyses and reverse transcription-polymerase chain reaction (RT-PCR) were used to predict variants' impact on protein structure and function.

Results: Disease-causing variants in the SLC22A5 were identified in all 24 subjects, and c.288delG, c.495C>A, c.774_775insTCG, c.824+1G>A, and c.1418G>T were novel. The novel variant c.824+1G>A caused a truncated protein p.Phe276Tyrfs*8.

Conclusions: We identified 13 variants in the SLC22A5 in 24 PCD patients, and five of these variants are novel mutations. c.824+1G>A was confirmed to alter mRNA splicing by reverse transcription PCR. Furthermore, our findings broaden the mutation spectrum of SLC22A5 and the understanding of the diverse and variable effects of PCD variants.
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http://dx.doi.org/10.1002/mgg3.901DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6732302PMC
September 2019

[Identification of a de novo interstitial 21q22.12q22.13 deletion in a patient with intellectual disability].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Jul;36(7):704-707

Prenatal Diagnosis Center of Hunan Province, Maternal and Child Health Care Hospital of Hunan Province, Changsha, Hunan 410008, China.

Objective: To explore the genetic basis of a child featuring intellectual disability, developmental delay and epilepsy.

Methods: Cytogenetic and molecular analysis including chromosomal karyotyping analysis, single nucleotide polymorphism array (SNP array) and qPCR were performed.

Results: The karyotype of the child was determined as 46, XX; SNP array: arr [19]21q22.12q22.13(36 860 195-38 801 482)×1 dn. A heterozygous 1.9 Mb microdeletion was detected at 21q22.12q22.13. qPCR has confirmed deletion of exon 1 of the DYRK1A gene, which has occurred de novo.

Conclusion: A 21q22 deletion was diagnosed with multiple genetic methods. Genotype-phenotype correlation suggested DYRK1A to be a candidate for intellectual disability.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.07.012DOI Listing
July 2019

[Prenatal diagnosis of monochorionic-diamniotic twins discordant for 45,X/46,XX mosaicism].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2019 Mar;36(3):260-262

Department of Medical Genetics, Maternal and Child Health Care Hospital of Hunan Province, Changsha, Hunan 410008, China.

Objective: To explore the prenatal screening and diagnosis for a pair of monochorionic-diamniotic (MCDA) twins discordant for 45,X/46,XX mosaicism.

Methods: Amniotic fluid samples were taken from both twins for whom non-invasive prenatal testing has signaled a high risk for sex chromosomal abnormality. Uncultured amniotic fluid was analyzed by fluorescence in situ hybridization (FISH) and single nucleotide polymorphism array (SNP-array). Conventional G-banded karyotyping analysis was performed on the cultured amniotic fluid.

Results: Metaphase chromosome analysis showed that one of the twins had a mos 45,X[11]/46,XX[26] karyotype, while the other had a normal karyotype. FISH and SNP-array applied on uncultured amniotic fluid revealed about 30% mosaicism in one of the twins. The twins were confirmed to be monozygotic by SNP-array analysis.

Conclusion: To avoid confusion arising from discordant karyotypes in MCDA twins with abnormal non-invasive prenatal testing (NIPT) results, dual amniocentesis should be carried out to obtain amniotic fluid samples for chromosomal as well as molecular analysis. To determine the ratio of 45,X and 46,XX cells in Turner syndrome can provide valuable information for prenatal genetic counseling.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2019.03.017DOI Listing
March 2019

[Genetic screening and prenatal diagnosis for high risk families of Fragile X syndrome].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2018 Oct;35(5):653-656

Center of Hunan Provincial Prenatal Diagnosis, Hunan Maternal and Child Health Hospital, Changsha, Hunan 410008, China.

Objective: To assess the value of genetic testing for Fragile X syndrome (FXS).

Methods: A domestically made diagnostic kit based Tri-primer-PCR method was used to detect mutations of the FMR1 gene among 6 pedigrees with unexplained intellectual disability. The results were verified by methylation PCR and Southern blotting.

Results: Pedigrees 1 and 6 were positive for the screening. In pedigree 1, a full-mutation allele with methylation was identified in the proband and his mother, which was passed on to the fetus. In pedigree 6, the proband was mosaic for a full-mutation allele and a pre-mutation allele. His sister was asymptomatic with a full-mutation. His mother carried pre-mutation allele, while his father and sister's baby were normal. The number of CGG repeats of the pedigrees 2 to 5 were in the normal range.

Conclusion: Genetic testing can provide an effective way to prevent FXS caused by FMR1 mutations and enable prenatal diagnosis for families with a high risk for the disease.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2018.05.007DOI Listing
October 2018

A de novo duplication of chromosome 9q34.13-qter in a fetus with Tetralogy of Fallot Syndrome.

Mol Cytogenet 2016 25;9:54. Epub 2016 Jul 25.

Prenatal Diagnosis Center of Province Hunan, The Maternal and Child Health Care Hospital of Hunan province, Changsha, Hunan 410008 People's Republic of China.

Background: Partial duplications of the distal 9q have been rarely reported in literatures. The key features included characteristic facial appearance, long fingers and toes, slight psychomotor retardation, heart murmur et al. But rare severe congenital heart defects (CHD) such as TOF were reported to be associated with 9qter duplications.

Case Presentation: A 23-year-old woman was referred for genetic counseling and prenatal diagnosis at 25(3/7) weeks of gestation due to her male fetus, diagnosed as Tetralogy of Fallot Syndrome (TOF) by prenatal ultrasound. SNP (Single nucleotide polymorphism) array revealed that the male fetus had a de novo 5.47 Mb duplication at 9q34.13-qter. Meanwhile, non-invasive prenatal testing (NIPT) using low coverage whole genome massively parallel sequencing of circulating cell-free fetal DNA (cffDNA) showed consistent results. Multiplex ligation-dependent probe amplification (MLPA) also confirmed the duplication at 9qter.

Conclusion: In this paper, we present an Asian fetus with TOF caused by a de novo 5.47 Mb duplication at 9q34.13-qter. Duplication of 9q34.13-qter should be considered as an etiological diagnosis in the case of TOF. Our prenatal diagnostic findings provide important information for genetic counseling on the male fetus and future pregnancies in this family. Chromosomal microarray analysis (CMA) remains the first-tier clinical diagnostic test for prenatal fetus with suspicious syndromes. We also highlight the high potential application of NIPT in the screening of sub-chromosomal rearrangement.
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http://dx.doi.org/10.1186/s13039-016-0267-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4960742PMC
July 2016

[Genetic analysis for 2 females carrying idic(Y)(p) and with sex development disorders].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2016 Jun;33(3):335-9

Maternal and Child Health Hospital of Hunan Province, Changsha, Hunan 410078, China.

Objective: To investigate the phenotype-genotype association of isodicentromere Y chromosome by analysis of two female patients carrying the chromosome with sexual development disorders.

Methods: The karyotypes of the two patients were determined by application of conventional G banding of peripheral blood samples and fluorescence in situ hybridization (FISH). PCR was applied to detect the presence of SRY gene.

Results: Conventional karyotype analysis showed case 1 to be a mosaic: mos.45,X[38]/46,X,+mar[151]/47,XY,+mar[5]/47,X,+mar × 2[2]/46,XY[4], FISH showed that 12 different cell lines were presented in the karyotype of case 1 and partial cell lines with SRY gene, the marker is an isodicentromere Y chromosome [idic(Y)(p)]. No mutation was found in the SRY gene. The karyotype of case 2 was mos.45,X[25]/46,X,+mar[35]. FISH showed the marker to be an idic(Y)(p) without the SRY gene.

Conclusion: The karyotype of patients carrying idic(Y)(p) seems unstable, and female patients have the characteristics of short stature and secondary sexual hypoplasia. Karyotype analysis combined with FISH analysis can accurately determine the breakpoint of idic(Y) and identify the types of complex mosaic, which may facilitate genetic counseling and prognosis.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2016.03.013DOI Listing
June 2016

[Application of next-generation DNA sequencing for prenatal testing of fetal chromosomal aneuploidies].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2015 Aug;32(4):533-7

Prenatal Diagnosis Center of Hunan Province, Maternal and Child Health Hospital of Hunan Province, Changsha, Hunan 410008, P. R. China.

Objective: To explore the value of next-generation sequencing for the non-invasive prenatal testing of fetal chromosomal aneuploidies.

Methods: Plasma from 4004 women with singleton pregnancy at a gestational age between 12-35(+5) weeks was collected prior to amniocentesis between April 19th 2011 and December 31st 2013. The samples were divided into three groups: (1) High risk for Down syndrome by biochemical screening; (2) Advanced maternal age; (3) Abnormalities by ultrasound or other methods. Plasma DNA extracted from above samples was sequenced at low coverage. Positive results were verified against the karyotypes of the fetuses. For those with negative results, the fetuses were followed up by telephone call for at least six months after birth.

Results: Among 4003 samples subjected to non-invasive prenatal diagnosis, 66 (1.65%) had a positive result. In group 1, 22 cases of trisomy 21 (T21), 3 cases of trisomy 18 (T18), 1 case of 13 trisomy (T13), 8 cases of 45,X and 2 cases of other chromosomal abnormality were detected. In group 2, 13 cases of T21, 2 cases of T18, 1 case of T13, 5 cases of 45,X, 2 cases of 47,XXN and 1 case of other chromosomal abnormality were detected. In group 3, 1 case of T21, 1 case of T18, 1 case of T13, and 3 cases of 47,XXN were detected. For 55 samples underwent prenatal diagnosis, 30 cases of T21 and 4 cases of T18 were discovered, which was consistent with the results of non-invasive prenatal diagnosis. For the 13 cases indicated as 45,X, 3 were verified by karyotype analysis, 2 were verified as mosaicism (45,X/46,XN), 8 were 46,XN (false positives). For the 5 cases indicated as 47,XXN, 2 were verified by karyotype analysis, the other 3 were 46,XN (false positives). Karyotypes of 3 cases suspected for other chromosomal abnormalities were all verified as 46,XN (false positive). Until May 1st 2014, telephone follow-up for those with negative screening results only identified a boy with facial abnormalities and developmental delay, which was similar to his older sister, combined karyotyping and fluorescence in situ hybridization analysis has verified the karyotype of the boy as 46,XY,rec(14)dup(14q)inv(14)(p12q14)pat.

Conclusion: Our results indicated that sequencing of plasma free DNA can rapidly detect fetal chromosomal aneuploidies. The method is non-invasive, and the results are highly consistent with karyotype analysis in terms of accuracy and specificity. Non-invasive testing can be used as an effective adjunct to conventional prenatal diagnostic methods, which can greatly reduce unnecessary invasive prenatal diagnosis. However, the sensitivity and accuracy for aneuploidy detection other than chromosome 13/18/21 still need to be improved.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2015.04.019DOI Listing
August 2015

[Prenatal genetic diagnosis for two Chinese families affected with oculocutaneous albinism type Ⅱ].

Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2014 Aug;31(4):424-7

Medical Genetic Laboratory, Maternal and Children Health Hospital of Hunan, Changsha, Hunan 410008, P. R. China.

Objective: To perform genotyping analysis and subsequent prenatal genetic diagnosis for two families affected with oculocutaneous albinism (OCA).

Methods: Direct sequencing of TYR and P genes was performed in two albino probands. Family members were screened for corresponding mutant alleles. Prenatal genetic diagnoses were performed at early pregnancy by chorionic villus sampling (CVS) at mid-pregnancy through amniocentesis.

Results: No mutations were detected in the TYR gene in either probands, whereas 4 heterozygous mutations of the P gene were found, namely c.406C>T, c.535A>G, c.808-2A>G and c.2180T>C, among which c.535A>G and c.808-2A>G were novel. In the first round prenatal genetic testing, both fetuses were found to have the same genotypes as the probands. Both families had decided to terminate the pregnancy after genetic counseling. In the second round testing, neither of the fetuses was found to be affected by genotyping. The pregnancies continued and two healthy fetuses were born.

Conclusion: OCA can be classified by genotyping, with which reliable prenatal diagnosis and feasible genetic counseling may be provided.
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http://dx.doi.org/10.3760/cma.j.issn.1003-9406.2014.04.003DOI Listing
August 2014
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