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1.
Article in Chinese | WPRIM | ID: wpr-922021

ABSTRACT

OBJECTIVE@#To analyze the clinical symptom and parental origin of patients with MECP2 duplication syndrome in order to provide a basis for genetic counseling and prenatal diagnosis.@*METHODS@#Clinical symptoms of four patients who were diagnosed with MECP2 duplication syndrome by copy number variation sequencing (CNV-Seq) were reviewed. The maternal origin of the duplications were verified.@*RESULTS@#All patients were males, and CNV-Seq revealed that they have all harbored a duplication in the Xq28 region spanning 0.32 ~ 0.86 Mb, which were derived from asymptomatic mothers. The clinical symptoms of three patients with three copies included delayed speech, intellectual disability, and muscular hypotonia, while the patient with four copies had died at 6 months after birth, with clinical symptoms including recurrent infections, seizures, and spasticity.@*CONCLUSION@#The four cases of MECP2 duplication syndrome have shown complete penetrance and have all derived from asymptomatic mothers. As a stable and reliable method, CNV-Seq can accurately detect the MECP2 duplication syndrome.


Subject(s)
Chromosomes, Human, X , DNA Copy Number Variations , Gene Duplication , Humans , Male , Mental Retardation, X-Linked , Methyl-CpG-Binding Protein 2/genetics , Phenotype
2.
Article in Chinese | WPRIM | ID: wpr-888381

ABSTRACT

OBJECTIVE@#To identify the pathogenic variants of 4 patients with hemolytic anemia of unknown cause.@*METHODS@#Peripheral blood samples of the patients and their family members were collected to extract DNA. The coding region and splice region in all exons of gene of erythrocyte related diseases were analyzed by using target sequence capture and high-throughput sequencing technology. Suspected pathogenic variants were verified by PCR combined Sanger sequencing technology.@*RESULTS@#Each of the probands was detected two compound heterozygous variants, and CDA II was diagnosed. Six variants were detected in the 4 probands, four variants were reported and the other two were first reported.@*CONCLUSION@#By high-throughput sequencing, gene variant of CDA II be analyzed fast and accurately. It is an effective supplement to convenional diagnostic methods. Furthermore, the novel variant sites have enriched the variant database of the SEC23B gene.


Subject(s)
Anemia, Dyserythropoietic, Congenital/genetics , Exons/genetics , High-Throughput Nucleotide Sequencing , Humans , Mutation , Vesicular Transport Proteins/genetics
3.
Article in Chinese | WPRIM | ID: wpr-888369

ABSTRACT

OBJECTIVE@#To analyze the prenatal diagnosis, parental verification and pregnancy outcome of 6 fetuses with 22q11.2 microdeletion syndrome.@*METHODS@#Copy number variation sequencing (CNV-seq)and chromosomal microarray analysis (CMA) were carried out for the fetuses.@*RESULTS@#The fetuses were found to harbor 2.54-3.2 Mb microdeletions of the 22q11.2 region, among which one was maternally inherited and one was paternally inherited. Two parents opted to continue with the pregnancy, and 4 chose induced labor. One fetus was found to have tetralogy of Fallot, while two carrier parents and one fetus appeared to have normal phenotype.@*CONCLUSION@#22q11.2 microdeletions identified upon prenatal diagnosis should be treated carefully, with ultrasonic scan and parental verification taken into account.


Subject(s)
DNA Copy Number Variations , Female , Fetus , Humans , Microarray Analysis , Pregnancy , Pregnancy Outcome , Prenatal Diagnosis , Ultrasonography, Prenatal
4.
Article in Chinese | WPRIM | ID: wpr-885513

ABSTRACT

Objective:To analyze the genetic test results and ultrasonographic markers of 41 fetuses with short femurs and their relationship.Methods:This study retrospectively analyzed 41 fetuses who were diagnosed with short femurs by ultrasound during 19-37 gestational weeks and underwent prenatal genetic examination at the First Affiliated Hospital of Zhengzhou University from January 2018 to June 2019. According to the results of genetic examination, these cases were divided into three groups after excluding three cases of variants of unknown significance: genetically normal group, chromosome variation (including chromosomal aneuploidy and pathogenic or likely pathogenic copy number variations) group, and gene mutation (including pathogenic or likely pathogenic gene mutations) group. According to the head circumference (HC), abdominal circumference (AC) and femur length (FL), Z FL, FL/HC, FL/AC, ΔZ H-F and ΔZ H+A-2F for each fetus were calculated. One-way ANOVA and LSD- t test were used for statistical analysis. Results:(1) Among the 41 fetuses with short femurs, there were 28 in the genetically normal group, five in the chromosome variation group, three with chromosome variations of unknown significance and five in the gene mutation group. (2) In the genetically normal, chromosome variation and gene mutation groups, Z FL values were -2.78±0.77, -4.36±0.69 and -4.69±0.70; FL/HC ratios were 0.178±0.011, 0.170±0.010 and 0.131±0.022; FL/AC ratios were 0.197±0.013, 0.186±0.011 and 0.151±0.017; ΔZ H-F values were 2.49±1.09, 3.53±1.28 and 8.17±1.30; ΔZ H+A-2F values were 4.44±2.00, 6.78±2.20 and 14.28±1.26, respectively. The differences in Z FL values between the genetically normal group and the chromosome variation group as well as the gene mutation group were statistically significant (both P<0.05); so were the differences in FL/HC, FL/AC and ΔZ H-F values between the gene mutation group and the genetically normal group as well as the chromosome variation group (all P<0.05) and in any pairwise comparison of ΔZ H+A-2F among the three groups (all P<0.05). Conclusions:The genetic etiology of fetal short femurs is mainly related to chromosomal variations (including chromosomal aneuploidy and pathogenic or likely pathogenic copy number variations) and gene mutation. In fetuses with chromosome variation and gene mutation, the degree of the femoral development delay relative to the development of HC and AC is worse than that in the normal genetic results group.

5.
Article in Chinese | WPRIM | ID: wpr-879589

ABSTRACT

OBJECTIVE@#To explore the genetic basis for a neonate with Pierre-Robin sequence.@*METHODS@#The child was subjected to chromosomal karyotyping, single nucleotide polymorphism array (SNP-array)-based comparative genomic hybridization and fluorescence in situ hybridization (FISH) analysis.@*RESULTS@#The child has featured microgthnia, glossoptosis, upper airway obstruction, mandible dehiscence and short neck. He was found to have a karyotype of 46,XY,der(4)add(4)(q34). Her mother's karyotype was determined as 46,XX,t(1;4)(q43;q34), while his father was 46,XY. SNP-array analysis suggested the child to be arr [hg19] 1q42.2q44 (232 527 958-249 202 755)× 3; 4q34.3q35.2 (168 236 901-190 880 409)× 1. The result of SNP-array for both parents was normal. FISH analysis confirmed that his mother has carried a balanced t(1;4)(q42;34) translocation. The aberrant chromosome 4 in the child has derived from his mother's translocation, which gave rise to partial 1q trisomy and 4q monosomy.@*CONCLUSION@#The 1q42.2q44 duplication and 4q34.3q35.2 deletion of the child probably underlay his abnormal phenotype of Pierre-Robin sequence.


Subject(s)
Child , Comparative Genomic Hybridization , Female , Humans , In Situ Hybridization, Fluorescence , Infant, Newborn , Male , Monosomy , Pierre Robin Syndrome/genetics , Translocation, Genetic , Trisomy/genetics
6.
Article in Chinese | WPRIM | ID: wpr-879554

ABSTRACT

OBJECTIVE@#To analyze the clinical phenotype and genetic variants in five Chinese pedigrees affected with Dysferlinopathy.@*METHODS@#Next generation sequencing (NGS) was carried out for the probands from the five pedigrees. Suspected variants were validated by Sanger sequencing. Pathogenicity of the variants was assessed based on the standards and guidelines by the American College of Medical Genetics and Genomics (ACMG).@*RESULTS@#Ten DYSF gene variants (including 5 frameshift variants, 3 splicing variants, 1 missense variant and 1 nonsense variant) were detected. Among these, c.1375dupA (p.Met459Asnfs*15), c.610C>T (p.Arg204X), c.1180+5G>A and c.1284+2T>C were known to be pathogenic, while c.4008_4010delCCTinsAC (p.Leu1337Argfs*8), c.1137_1169del (p.379_390del), c.754A>G(p.Thr252Ala), c.1175_1176insGCAGAGTG (p.Met394Serfs*7), c.3114_3115insCGGC (p.Arg1040Profs*74) and c.1053+3G>C were unreported previously. Of the six novel variants, c.1137_1169del, c.1175_1176insGCAGAGTG and c.3114_3115insCGGC were predicted as pathogenic (PVS1+PM2+PM3), c.4008_4010delCCTinsAC as likely pathogenic (PVS1+PM2), c.754A>G and c.1053+3G>C as variants of uncertain significance based on the ACMG standards and guidelines.@*CONCLUSION@#Variants of the DYSF gene probably underlay Dysferlinopathy in the patients among the five pedigrees. Above finding has enriched the spectrum of DYSF gene variants.


Subject(s)
Humans , Muscular Dystrophies, Limb-Girdle/genetics , Mutation , Pedigree , Phenotype , RNA Splicing
7.
Article in Chinese | WPRIM | ID: wpr-826534

ABSTRACT

OBJECTIVE@#To explore the genetic basis for an infant with multiple malformations including congenital heart disease and cleft palate.@*METHODS@#The child and his parents were subjected to conventional chromosomal karyotyping and low-coverage massively parallel copy number variation sequencing (CNV-seq) analysis.@*RESULTS@#The infant was found to have a 46,X,add(Y)(q11.23) karyotype, and his CNV-seq result was seq [hg19] 22q12.1q13.3 (29 520 001-51 180 000)× 3. His parents were found to be normal by both methods.@*CONCLUSION@#The additional chromosomal material found on Yq, verified as duplication of 22q12.1-q13.3, may account for the abnormal phenotype in this infant. CNV-seq has provided a useful complement for the diagnosis and more accurate information for genetic counseling.


Subject(s)
Abnormalities, Multiple , Genetics , Child , Chromosome Duplication , Chromosomes, Human, Pair 22 , Genetics , Cleft Palate , Genetics , DNA Copy Number Variations , Genetic Testing , Heart Defects, Congenital , Genetics , Humans , Infant , Karyotyping
8.
Article in Chinese | WPRIM | ID: wpr-868164

ABSTRACT

Objective:To explore the clinical application value and accuracy of cell-free fetal DNA (cff-DNA) technique in prenatal screening.Methods:The results of quantitative fluorescent PCR (QF-PCR) and karyotype of amniotic fluid cells were analyzed retrospectively in 2 398 monocyesis pregnant women who had been amniocentesis at the First Affiliated Hospital of Zhengzhou University from May 2013 to December 2019, and the results of 359 cases who had been examined by single-nucleotide polymorphism array (SNP array).Results:Cff-DNA test of 2, 398 cases indicated 987 cases of trisomy 21, 351 cases of trisomy 18, 135 cases of trisomy 13, 566 cases of sex chromosome abnormality, and 359 cases of other chromosome abnormality. Chromosome karyotype analysis detected 826 cases of trisomy 21, 213 cases of trisomy 18, 17 cases of trisomy 13, 221 cases of sex chromosome abnormality, and 26 cases of other chromosome abnormality. The detection rate were 83.69% (826/987), 60.68% (213/351), 12.59% (17/135), 39.04% (221/566) and 7.24% (26/359), respectively. QF-PCR detected 1 046 cases of trisomy and 188 cases of sex chromosomes abnormality, and the detection rate was 99.05% (1 046/1 056) and 85.07% (188/221), respectively. Compared with the abnormal number detected by chromosome karyotype analysis, 10 cases of trisomeric chimerism and 24 cases of sex chromosome were missed by QF-PCR. Among the 359 other chromosomal abnormalities detected by SNP array, 64 cases were consistent with the results of cff-DNA, and the detection rate was 17.83% (64/359), which was 10.59% higher than the karyotype result.Conclusions:Karyotype analysis is the gold standard for diagnosing chromosomal abnormalities. QF-PCR could diagnose common chromosome aneuploidy rapidly and accurately, and it could be used as an auxiliary detection technique for karyotype analysis. The incidence of sex chromosome chimerism is high, so missed diagnosis should be warned. SNP array could be given priority to verify chromosome microdeletion or microduplication detected by cff-DNA.

9.
Article in Chinese | WPRIM | ID: wpr-828318

ABSTRACT

OBJECTIVE@#To assess the value of chromosomal microarray analysis (CMA) for the analysis of 824 samples from miscarriage or stillbirth.@*METHODS@#Copy number variations (CNVs) in the abortic chorionic villi or stillbirth tissues were detected by CMA.@*RESULTS@#All specimens were successfully analyzed, among which 381 (46.2%) were diagnosed with chromosomal abnormalities, which included 312 (81.9%) numerical abnormalities, 66 (17.3%) structural abnormalities and 3 (0.8%) uniparental disomies. Among numerical chromosomal abnormalities, aneuploidies was most common (92.0%), with trisomy 16 and 45,X accounting for 41 (13.1%) and 63 (20.2%) of the cases, respectively. Among the 66 structural chromosomal aberrations, there were 26 (39.4%) CNVs duplications, 20 (30.3%) CNVs deletions, and 20 (30.3%) CNVs duplication and deletions. 33 CNVs were predicted as have a high chance to lead to a disease.@*CONCLUSION@#CMA is a reliable, robust, and high-resolution method for the analysis of miscarriage or stillbirth samples. Numerical aberrations, in particular chromosomal aneuploides, are the main cause for spontaneous abortions and stillbirths.


Subject(s)
Abortion, Spontaneous , Genetics , Chromosome Aberrations , Chromosome Disorders , Diagnosis , Genetics , DNA Copy Number Variations , Female , Humans , Microarray Analysis , Pregnancy , Stillbirth , Genetics
10.
Article in Chinese | WPRIM | ID: wpr-828316

ABSTRACT

OBJECTIVE@#To explore the genetic etiology of three pedigrees with a gestational history of fetal renal anomalies.@*METHODS@#Peripheral venous blood or skin samples were derived from the probands of the three pedigrees. Copy number variation sequencing (CNV-seq) was applied to detect alterations of genome CNVs.@*RESULTS@#The patient from pedigree 1 and the fetuses from pedigrees 2 and 3 all carried a heterozygous 17q12 deletion, with the size ranging from 1.4 Mb to 1.48 Mb encompassing the HNF1B gene.@*CONCLUSION@#The diagnosis of 17q12 microdeletion may be difficult during fetal period for its variable phenotypes. Alterations of chromosomal copy numbers need to be excluded in such patients.


Subject(s)
Chromosome Deletion , Chromosomes, Human, Pair 17 , Genetics , DNA Copy Number Variations , Fetus , Genetic Testing , Hepatocyte Nuclear Factor 1-beta , Genetics , Humans , Pedigree , Phenotype
11.
Article in Chinese | WPRIM | ID: wpr-827767

ABSTRACT

OBJECTIVE@#To detect genomic copy number variations (CNVs) among 145 children with unexplained mental retardation/developmental delay (MR/DD) by using low-depth whole-genome copy number variation sequencing (CNV-seq).@*METHODS@#Peripheral blood samples were collected from the patients and subjected to DNA extraction and CNV-seq. The results were analyzed by a combination of bioinformatic tools.@*RESULTS@#Forty-nine patients were found to carry a total of 67 CNVs with an average size of 5.27 Mb. Among these, 22 patients were assessed to carry MR/DD-related CNVs involving 21 syndromes. This gave a diagnostic rate of 15.17%(22/145) for CNVs associated with unexplained MR/DD. The corresponding regions of the 22 MR/DD-related CNVs in the human genome covered 174 MR/DD-related pathogenic genes, which have mapped to 18 sections on 10 chromosomes.@*CONCLUSION@#Genomic CNVs-related microdeletions/duplications account for a significant proportion of unexplained MR/DD, for which CNV-seq can provide an accurate diagnosis.

12.
Article in Chinese | WPRIM | ID: wpr-879482

ABSTRACT

OBJECTIVE@#To explore the genetic cause of a patient suspected for congenital ectodermal dysplasia with repeated hyperthermia and to assess the reproductive risk for his family.@*METHODS@#Medical whole-exome sequencing (WES) were used to detect single-nucleotide variations and low-coverage massively parallel copy number variation sequencing (CNV-seq) were employed to verify suspected CNVs. PCR and real-time quantitative PCR were applied to confirm the deletion of EDA gene.@*RESULTS@#The results of WES suggested that the patient carried a hemizygous deletion for chrX:69 243 016-69 395 730. CNV-seq indicated that the patient carried a deletion of approximately 0.12 Mb on Xq13.1, which encompassed the EDA gene. The PCR results confirmed that there was a hemizygous deletion of exons 3 to 8 of the EDA gene. The same deletion was not found in his mother.@*CONCLUSION@#The congenital ectodermal dysplasia of the patient may be attributed to deletion of exons 3 to 8 of the EDA gene, which could be de novo or derive from germline mosaicism of his mother. The WES and CNV-seq are of great value for the diagnosis of rare diseases.


Subject(s)
DNA Copy Number Variations , Ectodermal Dysplasia/genetics , Ectodysplasins/genetics , Exons , Genetic Testing , High-Throughput Nucleotide Sequencing , Humans , Mosaicism , Sequence Deletion , Whole Exome Sequencing
13.
Chinese Journal of Dermatology ; (12): 736-742, 2019.
Article in Chinese | WPRIM | ID: wpr-796840

ABSTRACT

Objective@#To evaluate the application value and significance of low-depth whole-genome sequencing for copy number variations (CNV-Seq) in the genetic diagnosis and prenatal diagnosis of X-linked ichthyosis (XLI) due to STS gene deletion.@*Methods@#Clinical data were collected from 3 616 subjects who received CNV-Seq, and single-gene test results were collected from 7 patients or pedigrees with ichthyosis in The First Affiliated Hospital of Zhengzhou University in 2018. The 3 616 samples included 2 891 prenatal samples from pregnant women (most were amniotic fluid samples, some fetal villus samples, very few umbilical blood samples) and 725 peripheral blood samples from other subjects. Genomic DNA was extracted from amniocytes or peripheral blood, and then subjected to CNV-Seq. Quantitative PCR (qPCR) and single nucleotide polymorphism (SNP) -comparative genomic hybridization (CGH) array were performed to verify the detected CNVs. Pathogenicity of the CNVs was analyzed according to the database of genomic variants (DGV) , database of genomic variation and phenotype in humans using ensembl resources (DECIPHER) , clinical genome resource (ClinGen) and online Mendelian inheritance in man (OMIM) .@*Results@#Of the 3 616 subjects receiving CNV-Seq, Xp22.31 deletion was identified in prenatal samples from 6 pregnant women, including 5 male and 1 female fetuses. The deleted fragment of Xp22.31 covered the XLI region containing the major gene STS. The parental CNV-Seq showed that the Xp22.31 deletion was spontaneous mutation in 2 of the 6 fetuses, and inherited from the parents in the other 4 fetuses. qPCR confirmed that the female fetus was a carrier of a complete heterozygous deletion of the STS gene, and there was a complete deletion of the STS gene in the other 5 male fetuses. SNP-CGH array also confirmed that the female fetus was heterozygous Xp22.31 deletion carrier, which was consistent with the CNV-Seq results. Ichthyosis gene panel sequencing in the 7 patients with ichthyosis showed 1 with harlequin ichthyosis, 2 with ichthyosis vulgaris, 3 with XLI, and no causative mutation in 1. CNV-Seq confirmed that Xp22.31 deletion existed in the above 2 patients with XLI due to STS gene deletion. Moreover, Xp22.31 duplication was found in 16 out of 3 616 subjects receiving CNV-Seq, but they were all individuals or fetuses with normal phenotype.@*Conclusions@#CNV-Seq is a stable and reliable method for screening whole-genome CNVs, and can be applied to genetic diagnosis and prenatal diagnosis of XLI due to STS gene deletion. The deletion of Xp22.31 fragment containing the STS gene can cause XLI, and the duplication of the same region is highly likely to be the polymorphic variation.

14.
Chinese Journal of Dermatology ; (12): 736-742, 2019.
Article in Chinese | WPRIM | ID: wpr-791777

ABSTRACT

Objective To evaluate the application value and significance of low-depth whole-genome sequencing for copy number variations(CNV-Seq)in the genetic diagnosis and prenatal diagnosis of X-linked ichthyosis(XLI)due to STS gene deletion. Methods Clinical data were collected from 3616 subjects who received CNV-Seq, and single-gene test results were collected from 7 patients or pedigrees with ichthyosis in The First Affiliated Hospital of Zhengzhou University in 2018. The 3616 samples included 2891 prenatal samples from pregnant women(most were amniotic fluid samples, some fetal villus samples, very few umbilical blood samples)and 725 peripheral blood samples from other subjects. Genomic DNA was extracted from amniocytes or peripheral blood, and then subjected to CNV-Seq. Quantitative PCR(qPCR)and single nucleotide polymorphism(SNP)-comparative genomic hybridization(CGH)array were performed to verify the detected CNVs. Pathogenicity of the CNVs was analyzed according to the database of genomic variants(DGV), database of genomic variation and phenotype in humans using ensembl resources (DECIPHER), clinical genome resource (ClinGen) and online Mendelian inheritance in man (OMIM). Results Of the 3616 subjects receiving CNV-Seq, Xp22.31 deletion was identified in prenatal samples from 6 pregnant women, including 5 male and 1 female fetuses. The deleted fragment of Xp22.31 covered the XLI region containing the major gene STS. The parental CNV-Seq showed that the Xp22.31 deletion was spontaneous mutation in 2 of the 6 fetuses, and inherited from the parents in the other 4 fetuses. qPCR confirmed that the female fetus was a carrier of a complete heterozygous deletion of the STS gene, and there was a complete deletion of the STS gene in the other 5 male fetuses. SNP-CGH array also confirmed that the female fetus was heterozygous Xp22.31 deletion carrier, which was consistent with the CNV-Seq results. Ichthyosis gene panel sequencing in the 7 patients with ichthyosis showed 1 with harlequin ichthyosis, 2 with ichthyosis vulgaris, 3 with XLI, and no causative mutation in 1. CNV-Seq confirmed that Xp22.31 deletion existed in the above 2 patients with XLI due to STS gene deletion. Moreover, Xp22.31 duplication was found in 16 out of 3616 subjects receiving CNV-Seq, but they were all individuals or fetuses with normal phenotype. Conclusions CNV-Seq is a stable and reliable method for screening whole-genome CNVs, and can be applied to genetic diagnosis and prenatal diagnosis of XLI due to STS gene deletion. The deletion of Xp22.31 fragment containing the STS gene can cause XLI, and the duplication of the same region is highly likely to be the polymorphic variation.

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