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1.
Chinese Journal of Endocrinology and Metabolism ; (12): 683-688, 2023.
Article in Chinese | WPRIM | ID: wpr-994376

ABSTRACT

Objective:To explore the clinical and genetic characteristics of 5α-reductase 2 deficiency syndrome(5α-RD2).Methods:Retrospective analysis of three cases of 5α-RD2 to summarize clinical data. Genetic testing was conducted using chromosome karyotyping analysis, whole-exome sequencing(WES), Sanger sequencing, and bioinformatics analysis. The effect of the novel variant on the structure of the 5α-reductase was evaluated by studying the homology modeling structure using SWISSMODEL and PyMoL.Results:The patients of all three cases have social gender as female. In Case 1, a 6-year-old patient sought medical attention due to abnormal external genitalia development. In Cases 2 and 3, 15-year-old patients presented with primary amenorrhea, and they showed masculinization of secondary sexual characteristics during puberty. In all three cases, the external genitalia exhibited varying degrees of masculinization, with clitoromegaly resembling a small penis and accompanying cryptorchidism. In Case 2, an hCG stimulation test was performed, and the testosterone/dihydrotestosterone(DHT) ratio was found to be 17.4. The karyotype of all three patients was 46, XY. Whole-exome sequencing(WES) detected SRD5A2 gene variants in all cases, with genotypes being p. Gln6Ter/p.Arg227Gln, p. Gln6Ter/p.Pro250Ala, and p. Arg227Ter/p.His89Tyr, respectively. Parental validation confirmed compound heterozygous mutations in all cases. The novel variant p. Pro250Ala was identified and classified as a likely pathogenic variant according to ACMG guidelines. Protein modeling analysis indicated that this variant may affect the binding of 5α-reductase 2 to NADPH. In Case 1, male gender was chosen, and a laparoscopic bilateral orchiopexy was performed. In Case 2, female gender was chosen, and testectomy and vaginoplasty were performed. The gender selection for Case 3 has not been definitively determined yet.Conclusions:Abnormal external genitalia is a common phenotype of 5α-RD2. After hCG stimulation test, there is a significant increase in the testosterone/dihydrotestosterone(DHT) ratio, which indicates that Sanger sequencing of the SRD5A2 gene can be directly performed. 5α-RD2 exhibits significant clinical heterogeneity, and WES can facilitate the differential diagnosis of 46, XY disorders of sex development. The study also reported a novel variant, p. Pro250Ala, which enriches the SRD5A2 gene variant database.

2.
Chinese Journal of Medical Genetics ; (6): 354-359, 2023.
Article in Chinese | WPRIM | ID: wpr-970932

ABSTRACT

OBJECTIVE@#To carry out genetic testing and prenatal diagnosis for a woman featuring moderate intellectual disability (ID).@*METHODS@#The patient had presented at the First Affiliated Hospital of Zhengzhou University on April 28, 2021. With informed consent, peripheral blood and amniotic fluid samples were collected for the extraction of genomic DNA. Pathogenic copy number variations (CNVs) were detected with CNV-seq, and single gene variants were detected by whole exome sequencing (WES) and Sanger sequencing. Candidate variant was verified by Sanger sequencing, and CNV-seq and multiplex ligation-dependent probe amplification (MLPA) were used to detect fetal CNVs.@*RESULTS@#The 23-year-old woman had moderate ID, sideway walking, and unstable holding. Ultrasonography at 18+3 weeks' gestation had revealed no fetal abnormality. No pathogenic CNV was detected in the woman by CNV-Seq, while WES revealed that she has harbored a heterozygous c.1675C>T (p.Arg559*) variant of the DLG4 gene, which was verified by Sanger sequencing. Based on guidelines from the American College of Medical Genetics and Genomics, the variant was predicted to be likely pathogenic (PVS1+PM2_supporting). Sanger sequencing has confirmed that the fetus has inherited this variant, and CNV-Seq also revealed that that fetus has harbored a 0.1 Mb heterozygous deletion at Xp21.1, which has encompassed the DMD gene, and the result was verified by MLPA.@*CONCLUSION@#The heterozygous c.1675C>T variant of the DLG4 gene probably underlay the mental retardation in this woman, and her fetus was found to harbor the same variant in addition with deletion of the DMD gene, which may predispose to ID type 62.


Subject(s)
Female , Humans , Pregnancy , Young Adult , Disks Large Homolog 4 Protein , DNA Copy Number Variations , Fetus , Genetic Testing , Intellectual Disability/genetics , Pregnant Women
3.
Chinese Journal of Experimental Ophthalmology ; (12): 960-965, 2022.
Article in Chinese | WPRIM | ID: wpr-955342

ABSTRACT

Objective:To analyze the clinical manifestations of congenital cataract in 12 families and gene variants causing the disease.Methods:The method of pedigree investigation was adopted.Clinical data of 27 patients from 12 Chinese Han families with congenital cataract were collected, and genomic DNA was extracted from peripheral blood samples of patients and family members.Candidate variants were screened by next generation sequencing and were verified by Sanger sequencing.Population frequency of the variants were obtained through the Genome Arrgregation Database (gnomAD).Pathogenicity of variants was analyzed through the Human Gene Mutation Database (HGMD), Database of Single Nucleotide Polymorphism (dbSNP) and PubMed, and the mutation effect was interpreted by protein prediction softwares including SIFT, PolyPhen_2 and MutationTaster.The conservation analysis of amino acid sequences of variants was performed by GERP+ + software.Diagnosis was confirmed by clinical ophthalmic phenotype, medical history and mutation analysis.This study adhered to the Declaration of Helsinki.The study protocol was approved by the Ethics Committee of the First Affiliated Hospital of Zhengzhou University (No.KS-2018-KY-36).Written informed consent was obtained from all subjects and their guardians.Results:Pathogenic genetic variants were found in all the 12 families, 9 of which had known pathogenic variants including MIP c.97C>T, GJA8 c.593G>A, CRYBA4 c.277T>C, CRYBB2 c.563G>A and c.436G>C, CRYGC c.470G>A, CRYGD c.70C>A, PAX2 c.70dupG as well as OCRL E5-E16dup, and 3 novel potential pathogenic variants including CRYGD c.422delG, ELP4 c.886C>A and CRYBB2 c.434G>C. CRYGD c.422delG could lead to the early termination of translation of protein products, which was pathogenic.The nucleotide and amino acid sites of ELP4 c.886C>A and CRYBB2 c.434G>C were highly conserved among species, and were predicted as harmful.The 12 families were consistent with co-segregation. Conclusions:CRYGD c.422delG, ELP4 c.886C>A and CRYBB2 c.434G>C may be novel pathogenic variants of congenital cataract.

4.
Chinese Journal of Medical Genetics ; (6): 474-478, 2022.
Article in Chinese | WPRIM | ID: wpr-928440

ABSTRACT

OBJECTIVE@#To analyze the clinical manifestations and causative gene variants of the choroideremia patients, and to help the patients bedifferential diagnosed by whole exome sequencing and provide theoretical basis for their genetic counseling.@*METHODS@#Clinical data of 3 families were collected and genomic DNA was extracted respectively from peripheral blood of patients and related subjects. Exome targeted sequencing was used to screen suspicious gene mutations. Sanger sequencing and quantitative PCR were used to verify the candidate mutations and investigate the mutation carrying status of other members of the family. The candidate mutations were searched through HGMD and PubMed databases for the pathogenicity reports, and the pathogenicity of candidate mutations was judged according to a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.@*RESULTS@#The proband of family 1 is c.1584_1587del (p.Val529Hisfs*6) variant hemizygote, whose daughter carries c.1584_1587del (p.Val529Hisfs*6) heterozygous variation. The proband of family 2 is a hemizygote with deletion of exons 10 to 15 (E10-15del), and her mother and sister carry the E10-15del heterozygous variation. In family 3, the proband is c.544delT (p.Cys182Valfs*14) variant hemizygote, and his mother is c.544delT (p.Cys182Valfs*14) heterozygote, but the father do not detect this variant. All the 3 families were detected pathogenic gene variations of CHM, two of which were known pathogenic variation and one of which was novel CHM gene c.544delT (p.C182Vfs*14) in this study. The c.544delT frameshift mutation of CHM gene can lead to the premature termination of the product protein translation and nonfunctioning protein. It is a pathogenic mutation according to ACMG guidelines.@*CONCLUSION@#The findings of this study expand the gene variation spectrum of choroideremia.


Subject(s)
Female , Humans , Choroideremia/genetics , Heterozygote , Mutation , Pedigree , Exome Sequencing
5.
Chinese Journal of Medical Genetics ; (6): 185-188, 2022.
Article in Chinese | WPRIM | ID: wpr-928385

ABSTRACT

OBJECTIVE@#To explore the genetic basis for a Chinese pedigree with two individuals suffering from congenital blindness.@*METHODS@#Clinical data and peripheral blood samples of the pedigree were collected. Whole exome sequencing was carried out. Suspected variants were verified by Sanger sequencing. Pathogenicity of candidate variants was validated through searching of PubMed and related databases, and analyzed with bioinformatics software.@*RESULTS@#Both patients had congenital blindness and a history of multiple fractures. Other features have included microphthalmia and cornea opacity. One patient had normal intelligence, whilst the other had a language deficit. Both patients were found to harbor compound heterozygous variants of the LRP5 gene, namely c.1007_1015delGTAAGGCAG (p.C336X), c.4400G>A (p.R1467Q) and c.4600C>T (p.R1534X). The first one was derived from their mother, whilst the latter two were derived from their father. None of the three variants was detected in their elder sister.@*CONCLUSION@#The compound heterozygous variants of c.1007_1015delGTAAGGCAG (p.C336X) and c.4600C>T (p.R1534X) of the LRP5 gene probably underlay the pathogenesis of the Osteoporosis-pseudoglioma syndrome in this pedigree. The clinical significance of the c.4400G>A (p.R1467Q) variant has remained uncertain. Above finding has enriched the mutational spectrum of Osteoporosis-pseudoglioma syndrome.


Subject(s)
Aged , Humans , China , Language , Low Density Lipoprotein Receptor-Related Protein-5/genetics , Mutation , Osteogenesis Imperfecta/genetics , Pedigree
6.
Chinese Journal of Medical Genetics ; (6): 1060-1063, 2021.
Article in Chinese | WPRIM | ID: wpr-921997

ABSTRACT

OBJECTIVE@#To analyze the clinical manifestations and gene variants of patients with blepharophimosis, ptosis and epicanthus inversus syndrome (BPES).@*METHODS@#Clinical data of 7 pedigrees affected with BPES were collected, and genomic DNA was extracted from peripheral blood samples of the probands and their relatives. All exons of the FOXL2 gene were subjected to Sanger sequencing. Those with negative findings were further screened by targeted capture and next generation sequencing (NGS) and microarray analysis. Pathogenicity of candidate variants were predicted by search of PubMed and related databases, and the impact of the variants was interpreted by protein prediction software. Diagnosis was confirmed by clinical phenotype, medical history and mutation analysis.@*RESULTS@#A pathogenic variant was identified in six of the 7 pedigrees, which included four known pathogenic variants and one novel FOXL2 c.299dupA variant. A heterozygous 3q22.3q23 deletion, which encompassed the FOXL2 gene, was identified in another pedigree.As predicted, the c.299dupA frameshift mutation of FOXL2 gene can lead to the premature termination of protein translation, which is pathogenic.@*CONCLUSION@#A novel and 5 known pathogenic variants have been identified in six pedigrees affected with BPES by the combined Sanger sequencing, target capture NGS and microarray analysis. Above findings have enabled genetic counseling and prenatal diagnosis for these pedigrees.


Subject(s)
Humans , Blepharophimosis/genetics , Forkhead Box Protein L2/genetics , Forkhead Transcription Factors/genetics , Mutation , Pedigree , Phenotype , Skin Abnormalities , Urogenital Abnormalities
7.
Chinese Journal of Medical Genetics ; (6): 134-137, 2021.
Article in Chinese | WPRIM | ID: wpr-879539

ABSTRACT

OBJECTIVE@#To perform prenatal diagnosis for a woman carrying a balanced translocation.@*METHODS@#Clinical phenotype of the woman and her first child was analyzed. Peripheral blood sample of the woman and amniotic fluid sample from two subsequent pregnancies were subjected to chromosomal karyotyping and copy number variation analysis through next-generation sequencing (NGS).@*RESULTS@#The karyotypes of the woman and her first child were determined as 46,XX,t(5;6)(p15:p23) and 46,XX,?der(5),t(5;6)(p15.32;p22.3), respectively. The karyotype of the amniocyte from her second pregnancy was 46,XN,t(5;6)(p15:p23). No pathogenic copy number variation was detected. The karyotype of her third pregnancy was 46,XN,?der(5),t(5;6)(p15.32;p22. 3), in addition with a 6.04 Mb deletion at 5p15.33p15.32 (20 000 - 6 060 000) and a 18.50 Mb duplication at 6p25.3p22.3 (160 000 - 18 660 000).@*CONCLUSION@#Combined karyotyping analysis and NGS has enabled detection of fetal copy number variations for a woman carrying a balanced chromosomal translocation.


Subject(s)
Child , Female , Humans , Pregnancy , DNA Copy Number Variations , Fetus , High-Throughput Nucleotide Sequencing , Karyotype , Karyotyping , Prenatal Diagnosis
8.
Chinese Journal of Ocular Fundus Diseases ; (6): 195-200, 2021.
Article in Chinese | WPRIM | ID: wpr-885862

ABSTRACT

Objective:To observe and analyze the pathogenic gene types and clinical phenotypes of Leber congenital amaurosis (LCA).Methods:A retrospective clinical study. Six patients with LCA confirmed by genetic testing and 18 family members were included in the study. The patients came from six unrelated families. The family was investigated with a specific hereditary eye disease enrichment panel which contained 463 known pathogenic genes and based on targeted exome capture technology first to indentify the potential pathogenic genes and mutations. Then the TULP1 , RPGRIP1 , GUCY2D pathogenic mutations were conformed by Sanger sequencing. The pathogenicity of the gene variation was searched through relevant databases and PubMed literature, and its function was explained by protein prediction software. Results:Of the 6 patients, 3 were males and 3 were females; the age was from 3 to 33 years. Nystagmus, finger pressing eyes, photophobia, and night blindness were seen in 5 cases; electroretinogram showed 3 cases of extinction or near extinction; and 4 cases of retinopathy. The results showed patients with compound heterozygous mutation of c.1318C> T and c.1142T> G, homozygous mutation ofc.1318C> T and compound heterozygous mutation of c.1153G> A and c.1561C> T of TULP1 in Family 1, Family 2 and Family 5, respectively. There were compound heterozygous mutations of RPGRIP1 c.391delG and c.1468-2A> G in Family 3 and c.715delA and c.1765C> T in Family 6, respectively. Homozygous mutation of c.3177_3178delAC of GUCY2D was found in Family 4.The parents of all six patients were carriers of corresponding heterozygous mutations. TULP1 gene c.1142T> G, RPGRIP1 gene c.391delG, c.715delA and c.1765C> T and GUCY2D gene c.3177_3178delAC mutations were novel mutations and unreported. The 381th amino acid locus of product protein of TULP1 gene was highly conserved among species. The protein prediction software predicted that the mutation pathogenic. The c.391delG, c.715delA and c.1765C> T mutations of RPGRIP1 gene and c.3177_3178delAC mutation of GUCY2D gene can lead to early translation termination of their product proteins, which are pathogenic variants. Conclusion:The pathogenic mutations of TULP1, RPGRIP1 and GUCY2D genes led to LCA 15, LCA 6 and LCA 1 in six families.

9.
Chinese Journal of Medical Genetics ; (6): 28-32, 2020.
Article in Chinese | WPRIM | ID: wpr-781301

ABSTRACT

OBJECTIVE@#To explore the genetic basis of an infant featuring congenital cataract, developmental delay and proteinuria.@*METHODS@#Clinical data and peripheral blood samples of the family were collected. Potential variants were screened by using targeted capture and high-throughput sequencing on a NextSeq 500 platform. Suspected variant was verified by quantitative PCR. Pathogenicity of the candidate variant was predicted based on clinical presentation and laboratory tests.@*RESULTS@#The infant's phenotypes included brain development retardation and proteinuria. Cranial MRI indicated widening of cerebral fissure, bilateral frontal and temporal subarachnoid cavities, and dysplasia of white matter myelination in posterior angular of ventricle. A novel duplication of exons 5 to 16 of the OCRL gene was found in the patient. His mother has carried the same duplication variant.@*CONCLUSION@#The duplication variant of the OCRL gene probably underlies the oculo-cerebro-renal syndrome in the infant. Due to the heterogeneity of its clinical manifestation, pertinent genetic detection is essential for acurrate diagnosis of patients who have the related phenotypes.


Subject(s)
Humans , Infant , Exons , Genetics , Genetic Testing , Oculocerebrorenal Syndrome , Genetics , Phenotype , Phosphoric Monoester Hydrolases , Genetics
10.
Chinese Journal of Medical Genetics ; (6): 28-32, 2020.
Article in Chinese | WPRIM | ID: wpr-798650

ABSTRACT

Objective@#To explore the genetic basis of an infant featuring congenital cataract, developmental delay and proteinuria.@*Methods@#Clinical data and peripheral blood samples of the family were collected. Potential variants were screened by using targeted capture and high-throughput sequencing on a NextSeq 500 platform. Suspected variant was verified by quantitative PCR. Pathogenicity of the candidate variant was predicted based on clinical presentation and laboratory tests.@*Results@#The infant’s phenotypes included brain development retardation and proteinuria. Cranial MRI indicated widening of cerebral fissure, bilateral frontal and temporal subarachnoid cavities, and dysplasia of white matter myelination in posterior angular of ventricle. A novel duplication of exons 5 to 16 of the OCRL gene was found in the patient. His mother has carried the same duplication variant.@*Conclusion@#The duplication variant of the OCRL gene probably underlies the oculo-cerebro-renal syndrome in the infant. Due to the heterogeneity of its clinical manifestation, pertinent genetic detection is essential for acurrate diagnosis of patients who have the related phenotypes.

11.
Chinese Journal of Medical Genetics ; (6): 509-513, 2020.
Article in Chinese | WPRIM | ID: wpr-826545

ABSTRACT

OBJECTIVE@#To identify pathogenic variants in two families with patients suspected for Joubert syndrome(UBST) by cerebellar vermis hypoplasia.@*METHODS@#Clinical data and peripheral venous blood and skin tissue samples were collected for the extraction of genomic DNA. Potential variants were screened by using targeted capture and next generation sequencing. Suspected variants were validated by PCR and Sanger sequencing. The frequency of the variants in the population was calculated. Pathogenicity of the variants was predicted by following the guidelines of the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was provided to these families upon subsequent pregnancy.@*RESULTS@#The proband of family 1 was found to harbor homozygous c.2072delT (p.F691S*fs19) frameshift variant of the AHI1 gene, which may cause premature termination of translation of the Abelson helper integration site 1 after the 691st amino acid. The proband of family 2 was found to harbor compound heterozygous variants of the CPLANE1 gene, namely c.7243dupA (p.T2415Nfs*7) and c.8001delG (p.K2667Nfs*31), which can respectively lead to premature termination of translation of ciliogenesis and planar polarity effector 1 after the 2145th and 2667th amino acids. All of the three variants were previously unreported, and were predicted to be pathogenic by bioinformatic analysis.@*CONCLUSION@#The AHI1 c.2072delT and CPLANE1 c.7243dupA and c.8001delG variants probably underlay JBTS3 in family 1 and JBTS17 in family 2, respectively. Based on above results, prenatal diagnosis may be offered to the affected families upon their subsequent pregnancies.


Subject(s)
Female , Humans , Pregnancy , Abnormalities, Multiple , Diagnosis , Genetics , Adaptor Proteins, Vesicular Transport , Genetics , Cerebellum , Congenital Abnormalities , Eye Abnormalities , Diagnosis , Genetics , Genetic Testing , Genetic Variation , Kidney Diseases, Cystic , Diagnosis , Genetics , Membrane Proteins , Genetics , Mutation , Prenatal Diagnosis , Retina , Congenital Abnormalities
12.
Chinese Journal of Medical Genetics ; (6): 709-712, 2020.
Article in Chinese | WPRIM | ID: wpr-826504

ABSTRACT

OBJECTIVE@#To explore the clinical and genetic characteristics of five pedigrees affected with hereditary spastic paraplegia(HSP).@*METHODS@#Clinical data of the five pedigrees was collected, and high-throughput sequencing was carried out to detect potential variants. Sanger sequencing were used to verify the results.@*RESULTS@#The probands of pedigree 1 and 2 were found to harbor heterozygous SPAST gene variants, namely c.1196C>T and c.1523T>A. The proband of pedigree 3 harbored compound heterozygous variants of FA2H gene (c.61G>C and c.688G>A). Proband from pedigree 4 harbored compound heterozygous variants of SPG11 gene (c.6812+4_6812+7delAGTA and c.915delT). The proband of pedigree 5 harbored compound heterozygous variants of SPG7 gene (c.1703_1704delAG and c.1937-1G>C). Based on the American College of Medical Genetics and Genomics(ACMG) guidelines, all variants were predicted to be likely pathogenic. Among these, SPAST gene c.1523T>A, FA2H gene c.61.G>C, SPG11 gene splicing region c.6812+4_6812+7delAGTA, c.915delT, SPG7 gene c.1703_1704delAG and splicing region c.1937-1G>C variants were unreported previously.@*CONCLUSION@#The probands of pedigrees 1 and 2 were diagnosed with autosomal dominant hereditary spastic paraplegia type 4, for which pedigree 2 showed incompletely penetrance. Pedigrees 3, 4, and 5 were diagnosed with autosomal recessive hereditary spastic paraplegia type 35, 11 and 7, respectively. Above result provided a reference for clinical diagnosis and genetic counseling for the affected pedigrees.

13.
Chinese Journal of Medical Genetics ; (6): 1340-1343, 2020.
Article in Chinese | WPRIM | ID: wpr-879494

ABSTRACT

OBJECTIVE@#The CYP4V2 gene of two pedigrees affected with Bietti crystalline corneoretinal dystrophy was analyzed to indentify the cause of the disease and provide a basis for clinical diagnosis.@*METHODS@#The probands were subjected to next generation sequencing (NGS). Suspected variants were verified by Sanger sequencing. Pathogenicity of the variants were searched through relevant databases and PubMed by following the ACMG guidelines.@*RESULTS@#A homozygous variant in the CYP4V2 gene c. (802-8) _810delTCATACAGGTCATCGCTinsGC was detected in proband from pedigree 1, parents did not detect; CYP4V2 genes c. (802-8)_810delTCATACAGGTCATCGCTinsGC and c. 958 C>T (p.Arg320X) compound heterozygous variants existed in the proband of pedigree 2,both parents were variant carriers. The results of Sanger sequencing showed that the variant of CYP4V2 gene in the two families was consistent with the NGS sequencing. The c. (802-8)_810delTCATACAGGTCATCGCTinsGC of CYP4V2 gene was splicing variant, and both splicing variant and nonsense variant could produce truncated nonfunctional protein products. Based on standards and guidelines by American College of Medical Genetics and Genomics, the CYP4V2 genes c. (802-8)_810del TCATACAGGTCATCGCTinsGC and c. 958 C>T (p.Arg320X) were predicted to be pathogenic variants (PVS1+PS1+PM2+PM3).@*CONCLUSION@#The homozygous variant c. (802-8) _810delTCATACAGGTCATCGCTinsGC and the complex heterozygous variants c. (802-8) _810delTCATACAGGTCATCGCTinsGC and c.958C>T (p.Arg320X) in CYP4V2 gene are the cause of the disease in the probands of two pedigrees , respectively.


Subject(s)
Humans , Corneal Dystrophies, Hereditary/pathology , Cytochrome P450 Family 4/genetics , Genetic Variation , Mutation , Pedigree , Phenotype , Retinal Diseases/pathology
14.
Chinese Journal of Medical Genetics ; (6): 910-913, 2019.
Article in Chinese | WPRIM | ID: wpr-797493

ABSTRACT

Objective@#To explore the genetic basis for an infant featuring developmental delay, hand deformity and hypertonia of extremities.@*Methods@#Clinical data and peripheral blood samples of the proband and her parents were collected. Following DNA extraction, potential mutations were screened on an Ion PGM platform using a gene panel. Suspected mutation was verified by PCR and Sanger sequencing.@*Results@#A novel heterozygous nonsense mutation, c. 2521C>T(p.R841X), was identified in the NIPBL gene. The mutation may cause premature termination of translation of the adhesion protein loading factor at 841st amino acids. The same mutation was not found in her parents and 931 healthy controls, and was absent from public databases including ExAC and 1000G. Bioinformatic analysis suggested the mutation to be disease causing.@*Conclusion@#The c. 2521C>T (p.R841X) mutation of the NIPBL gene probably underlies the Cornelia De Lange syndrome in the infant. Prenatal diagnosis may be provided to this family upon their subsequent pregnancy.

15.
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.

16.
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.

17.
Chinese Journal of Medical Genetics ; (6): 829-833, 2019.
Article in Chinese | WPRIM | ID: wpr-776795

ABSTRACT

OBJECTIVE@#To explore the genetic basis for a family affected with mental retardation combined with autism.@*METHODS@#For the family featuring X-linked recessive inheritance of mental retardation combined with autism, clinical data and peripheral blood samples were collected. Potential mutations of genes associated with intellectual impairment were sequenced with an Ion PGM platform. Suspected mutations were verified with a PCR-Sanger sequencing method.@*RESULTS@#The patient with mental retardation had mild abnormal electroencephalograph(EEG), while brain MRI and CT scans showed no obvious abnormality. Two ABC (autism behavior checklist) testing scores were 73 and 66 when he was 7- and 13-year-old, respectively. A novel hemizygous mutation, c.64C>T (p.L22F), was detected in the GRIA3 gene in the patient, for which his mother was a heterozygous carrier. The mutation site was predicted to be possibly damaging and disease causing by PolyPhen_2 and MutationTaster.@*CONCLUSION@#The novel hemizygous c.64C>T (p.L22F) mutation of the GRIA3 gene probably underlies the phenotypes of mental retardation combined with autism in this family. Considering the variable clinical manifestation of mental retardation and genetic heterogeneity of autism, genetic testing is essential for making the correct diagnosis.


Subject(s)
Adolescent , Child , Humans , Male , Autistic Disorder , Genetics , Intellectual Disability , Genetics , Mental Retardation, X-Linked , Genetics , Mutation , Receptors, AMPA , Genetics
18.
Chinese Journal of Medical Genetics ; (6): 910-913, 2019.
Article in Chinese | WPRIM | ID: wpr-776777

ABSTRACT

OBJECTIVE@#To explore the genetic basis for an infant featuring developmental delay, hand deformity and hypertonia of extremities.@*METHODS@#Clinical data and peripheral blood samples of the proband and her parents were collected. Following DNA extraction, potential mutations were screened on an Ion PGM platform using a gene panel. Suspected mutation was verified by PCR and Sanger sequencing.@*RESULTS@#A novel heterozygous nonsense mutation, c.2521C>T(p.R841X), was identified in the NIPBL gene. The mutation may cause premature termination of translation of the adhesion protein loading factor at 841st amino acids. The same mutation was not found in her parents and 931 healthy controls, and was absent from public databases including ExAC and 1000G. Bioinformatic analysis suggested the mutation to be disease causing.@*CONCLUSION@#The c.2521C>T (p.R841X) mutation of the NIPBL gene probably underlies the Cornelia De Lange syndrome in the infant. Prenatal diagnosis may be provided to this family upon their subsequent pregnancy.


Subject(s)
Female , Humans , Infant , Pregnancy , De Lange Syndrome , Diagnosis , Genetics , Heterozygote , Mutation , Prenatal Diagnosis , Proteins , Genetics
19.
Chinese Journal of Medical Genetics ; (6): 1115-1119, 2019.
Article in Chinese | WPRIM | ID: wpr-776733

ABSTRACT

OBJECTIVE@#To explore the genetic basis for a boy with mental retardation.@*METHODS@#Clinical data and peripheral blood samples of the family were collected. Potential variants were screened by using a panel for genes associated with intellectual impairment. Suspected variants were verified by PCR and Sanger sequencing.@*RESULTS@#The child presented with mental retardation, language delay and poor self-care. Imaging analysis showed widening of brain fissures and subarachnoid space, and dysplasia of corpus callosum. Three novel heterozygous variants, namely c.1705T to C (p.S569P), c.1708dupC (p.R570Pfs*80) and c.2273delA (p.N758Tfs*22), were identified in the TRAPPC9 gene. The mother of the proband has carried the c.1708dupC (p.R570Pfs*80) and c.1705T to C (p.S569P) variants, while his father has carried the c.2273delA (p.N758Tfs*22) variant.@*CONCLUSION@#The compound heterozygous variants of the TRAPPC9 gene probably underlie the disease in this family. Considering the clinical and genetic heterogeneity of mental retardation, genetic testing is essential for attaining diagnosis for patients with the relevant phenotype.


Subject(s)
Child , Humans , Male , Carrier Proteins , Genetics , Genetic Testing , Heterozygote , Intellectual Disability , Genetics , Mutation , Phenotype
20.
Chinese Journal of Medical Genetics ; (6): 1127-1129, 2019.
Article in Chinese | WPRIM | ID: wpr-776730

ABSTRACT

OBJECTIVE@#To analyze a family with recurrent fetal copy number variations (microdeletion and microduplication, respectively) of 1p31.1 using single nucleotide polymorphism-based array (SNP-array) and G banding chromosomal karyotyping.@*METHODS@#Amniocentesis and chorionic villus sampling were performed for a woman during the two pregnancies. Whole genome SNP-array was used to detect genomic imbalance of the fetus. The couple was also subjected to G-banding chromosomal analysis and SNP-array analysis.@*RESULTS@#SNP-array showed a 1p31.1 (70 164 686-83 474 843) ×1 and a 1p31.1 (70 164 686-83 479 747) ×3 in the fetuses during the two pregnancies, respectively. SNP array results of the couple appeared to be normal. The mother of the fetuses had a 46,XX,inv(1)(p31.1p32.1) karyotype.@*CONCLUSION@#The paracentric inversion in chromosome 1 in the gravida probably underlies the recurrent 1p31.1 copy number variations in the fetuses. SNP-array combined with G banding chromosomal analysis are suitable for prenatal diagnosis for recurrent microdeletion and microduplication in the same chromosomal region, and can provide detailed information for genetic counseling.


Subject(s)
Female , Humans , Pregnancy , Amniocentesis , Chromosomes, Human, Pair 1 , Genetics , DNA Copy Number Variations , Fetus , Karyotyping , Polymorphism, Single Nucleotide , Prenatal Diagnosis
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