Analysis of genotypes and phenotypes of three children with Cornelia de Lange syndrome / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical phenotype and results of genetic testing in three children with Cornelia de Lange syndrome (CdLS).@*METHODS@#Clinical data of the children and their parents were collected. Peripheral blood samples of the pedigrees were collected for next generation sequencing analysis.@*RESULTS@#The main clinical manifestations of the three children have included growth delay, mental retardation, peculiar facies and other accompanying symptoms. Based on the criteria proposed by the International Diagnostic Consensus, all three children were suspected for CdLS. As revealed by whole exome sequencing, child 1 has harbored NIPBL gene c.5567_5569delGAA insTAT missense variant, child 2 has harbored SMC1A gene c.607A>G missense variant, and child 3 has harbored HDAC8 gene c.628+1G>A splicing variant. All of the variants were de novo in origin.@*CONCLUSION@#All of the children were diagnosed with CdLS due to pathogenic variants of the associated genes, among which the variants of NIPBL and HDAC8 genes were unreported previously. Above finding has enriched the spectrum of pathogenic variants underlying CdLS.

Prenatal diagnosis for a fetus with Walker-Warburg syndrome / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology for a fetus with Walker-Warburg syndrome(WWS).@*METHODS@#A fetus with WWS diagnosed at Gansu Provincial Maternity and Child Health Care Hospital in June 9, 2021 was selected as the study subject. Genomic DNA was extracted from amniotic fluid sample of the fetus and peripheral blood samples from its parents. Trio-Whole exome sequencing (trio-WES) was carried out. Candidate variants were verified by Sanger sequencing.@*RESULTS@#The fetus was found to harbor compound heterozygous variants of the POMT2 gene, namely c.471delC (p.F158Lfs*42) and c.1975C>T (p.R659W), which were respectively inherited from its father and mother. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), they were respectively rated as pathogenic (PVS1+PM2_Supporting+PP4) and likely pathogenic (PM2_Supporting+PM3+PP3_Moderate+PP4).@*CONCLUSION@#Trio-WES may be used for the prenatal diagnosis of WWS. The compound heterozygous variants of the POMT2 gene probably underlay the disorder in this fetus. Above finding has expanded the mutational spectrum of the POMT2 gene and enabled definite diagnosis and genetic counseling for the family.

Genetic analysis of a child patient with rare fibrochondrogenesis due to COL11A1 gene variant / 中华医学遗传学杂志

OBJECTIVE@#To analyze the clinical data and genetic characteristics of a child with fibrocartilage hyperplasia type 1 (FBCG1).@*METHODS@#A child who was admitted to Gansu Provincial Maternity and Child Health Care Hospital on January 21, 2021 due to severe pneumonia and suspected congenital genetic metabolic disorder was selected as the study subject. Clinical data of the child was collected, and genomic DNA was extracted from peripheral blood samples from the child and her parents. Whole exome sequencing (WES) was carried out, and candidate variants were verified by Sanger sequencing.@*RESULTS@#The patient, a 1-month-old girl, had presented with facial dysmorphism, abnormal skeletal development, and clubbing of upper and lower limbs. WES revealed that she has harbored compound heterozygous variants c.3358G>A/c.2295+1G>A of the COL11A1 gene, which has been associated with fibrochondrogenesis. Sanger sequencing has verified that the variants have been respectively inherited from her father and mother, both of whom were phenotypically normal. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), the c.3358G>A variant was graded as likely pathogenic (PM1+PM2_Supporting+PM3+PP3), and so was the c.2295+1G>A variant (PVS1＋PM2_Supporting).@*CONCLUSION@#The compound heterozygous variants c.3358G>A/c.2295+1G>A probably underlay the disease in this child. Above finding has facilitated definite diagnosis, genetic counseling for her family.

Gene variation analysis and prenatal diagnosis for 54 families with oculocutaneous albinism / 中华围产医学杂志

Objective:To investigate the pathogenic gene locus and prenatal genetic diagnosis of 54 families with oculocutaneous albinism (OCA).Methods:This retrospective study enrolled 54 OCA probands and their families from Gansu Province Maternal and Child Health Care Hospital from May 2014 to May 2020. TYR gene variation screening was performed on the probands by Sanger sequencing. Those with negative results were analyzed by high-throughput sequencing, and further verification was performed on their parents by Sanger sequencing. Among the 54 families, 15 ml amniotic fluid were collected from 16 women at 18-21 gestational weeks in their subsequent pregnancy. Sanger sequencing combined with short tandem repeats sequence for linkage analysis were performed for genetic analysis. All data were analyzed using descriptive statistical analysis. Results:Out of the 54 OCA probands, 48 were diagnosed as OCA1, five were OCA2 and one was OCA4 based on the Sanger sequencing and high-throughput sequencing detection. A total of 26 different variation sites were involved in the 48 OCA1 probands, including 15 missense mutations, five nonsense mutations, three splicing mutations, and three frame-shift mutations, among which, c.929insC (29%, 28/96) was the most frequent mutation, followed by c.896G>A (11%, 11/96), c.832C>T (8%, 8/96) and c.703T>C (5%, 5/96). The diagnosis was confirmed in all 16 fetuses in the 16 families that underwent prenatal diagnosis. Five of them were affected and their mothers chose to terminate the pregnancies, the other 11 pregnancies continued to delivery, including seven heterozygous carriers and four fetuses without the same pathogenic allele as the proband. Maternal contamination was excluded in all prenatal samples using short tandem repeat for linkage analysis. All 11 children were in good health during telephone follow-up one month after birth. Postnatal validations were consistent with the prenatal tests.Conclusions:Genetic diagnosis could accurately identify various types of OCA and help to provide prenatal diagnosis and fertility consultation for subsequent pregnancies.

Analysis of genetic variant in a child with concomitant spinal muscular atrophy and Citrin protein deficiency / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis for a child with concomitant spinal muscular atrophy (SMA) and Citrin protein deficiency.@*METHODS@#The child was subjected to whole exome sequencing by using target sequence capture high-throughput sequencing. Candidate variants were verified by Sanger sequencing. The SMN genes of the patient were also analyzed through multiplex ligation-dependent probe amplification (MLPA).@*RESULTS@#The patient was found to carry homozygous deletion of exons 7 and 8 of the SMN1 gene, for which his parents were both carriers. The patient also carried compound heterozygous variants c.1737G>A and IVS16ins3kbof the SLA25A13 gene, in addition with compound heterozygous variants c.948G>A and c.2693T>C of the POLG gene, for which his parents were carriers, too.@*CONCLUSION@#Variants of the SLC25A13 gene probably underlay the deficiency of Citrin protein, which may lead to neonatal intrahepatic cholestasis (NICCD). The patient also had SMA. The compound heterozygous variants c.948G>A and c.2693T>C of the POLG gene are likely to cause mitochondrial DNA deletion syndrome type 4A, though other types of mitochondrial disease cannot be excluded.

Identification of a novel PAX6 mutation in a sporadic case with congenital aniridia / 中华医学遗传学杂志

OBJECTIVE@#To identify mutation of the PAX6 gene in a patient with congenital aniridia.@*METHODS@#DNA was extracted from peripheral blood sample of the patient and analyzed by direct PCR-Sanger sequencing.@*RESULTS@#The proband was found to harbor a heterozygous c.239T>A (p.Ile80Asn) mutation of the PAX6 gene. The same mutation was not found in his parents and 150 healthy controls.@*CONCLUSION@#A novel mutation of the PAX6 gene has been identified in a sporadic case with congenital aniridia.

Clinical and cyto-molecular genetics analysis of trisomy 12p in neonates: a case report / 临床儿科杂志

Objective To explore the clinical features, cytogenetic and molecular genetics characteristics of trisomy 12 p in neonates. Method The clinical data were reviewed in a neonate with trisomy 12 p confirmed by routine G-banding chromosome karyotype analysis, high throughput sequencing chromosome copy number variation analysis (CNV) and lymphocyte interphase fluorescence in situ hybridization (FISH) . Results The chromosome karyotype in peripheral blood of the neonate was 47, XX, +mar, and the karyotypes of her parents were normal. CNV detected a regional duplication of 12 p13.33-p11.1 (160001-34860000) with a fragment size of 34.7 Mb. Peripheral blood lymphocyte interphase FISH showed that there were 3 signals in the short arm of chromosome 12 in all interphase nuclei of the neonate, and no chimera existed. It was finally confirmed to be trisomy 12 p. Conclusion The combination of clinical features, peripheral blood karyotype analysis, CNV and FISH techniques can effectively confirm the diaganosis of trisomy 12 p.

Prenatal diagnosis and PAH gene mutations in 55 pedigrees with phenylketonuria / 中华围产医学杂志

Objective To investigate phenylalanine hydroxylase ( PA H ) gene mutations and to perform prenatal diagnosis in 55 pedigrees with classical phenylketonuria (PKU). Methods Subjects of this study were 55 probands diagnosed with PKU in the Gansu Provincial Maternal and Child Health Care Hospital from 2013 to 2017 and their pedigrees. Sanger sequencing/Multiplex ligation-dependent probe amplification (MLPA) was used to investigate PA H gene mutations in these probands and their parents. Sanger sequencing/MLPA, linkage analysis of three common short tandem repeats (STR) including PAH-26, PAH-STR and PAH-32 in the PA H gene and paternity testing were used in combination for prenatal diagnosis of 60 fetuses in the 55 pedigrees. Results Among the 110 alleles in the 55 probands, 108 mutant alleles (98.2%) were found by Sanger sequencing. The 108 mutant alleles located in 38 regions resulting in 22 missense mutations, nine splice site mutations, five nonsense mutations and two microdeletion. The most common mutations were c.728G>A (22.2%, 24/108), c.442-1G>A (5.6%, 6/108), c.611A>G (5.6%, 6/108), c.764T>C (5.6%, 6/108), c.1068C>A (5.6%, 6/108) and c.331C>T (4.6%, 5/108). Loss of heterozygosity in 4-5 and 4-7 exons were detected by MLPA in two probands, in which only one mutation was unidentified. Prenatal diagnosis for the 60 fetuses were successfully performed. Among them, 17 fetuses (28.3%) were affected, 29 fetuses (48.3%) were heterozygous carriers and fetuses 14(23.4%) were unaffected ones. Conclusions Combination of Sanger sequencing/MLPA, linkage analysis and paternity testing could provide accurate prenatal diagnosis in pedigrees with PKU.

Analysis of Risk Factors of Hemorrhagic Transformation after Thrombolytic Therapy Using Recombinant Tissue Plasminogen Activator in Patients with Acute Ischemic Stroke / 中国医科大学学报

Objective To investigate the risk factors associated with hemorrhagic transformation after administration of thrombolytic therapy using recombinant tissue plasminogen activator (rt-PA) in patients diagnosed with acute ischemic stroke.Methods The design for this research was a case-control study-21 patients with hemorrhagic transformation after administration of thrombolytic therapy using rt-PA were categorized as cases,and 63 patients without hemorrhagic transformation after administration of thrombolytic therapy using rt-PA were categorized as controls.Univariate and multivariate logistic regression analysis were performed to analyze the risk factors associated with hemorrhagic transformation after administration of thrombolytic therapy using rt-PA in patients diagnosed with acute ischemic stroke.Results Results of univariate analysis showed that positive baseline National Institutes of Health Stroke Scale (NIHSS) scores ＞ 10,hypertension,baseline systolic blood pressure (SBP) ≥ 140 mmHg,increased blood glucose level,history of atrial fibrillation,and cerebrovascular disease (CVD) were significantly higher in the case group than in the control group.Results of multivariate logistic regression analysis showed that baseline SBP ≥ 140 mmHg (OR =14.59,95％ CI:1.63-130.95),increased blood glucose level (OR =9.92,95％ CI:0.97-101.24),and history of CVD (OR =10.75,95％ CI:1.76-65.78) were independent risk factors associated with hemorrhagic transformation after administration of thrombolytic therapy using rt-PA in patients diagnosed with acute ischemic stroke.Conclusion Baseline SBP ≥ 140 mmHg,increased blood glucose level,and history of CVD were observed to be independent risk factors associated with hemorrhagic transformation after administration of thrombolytic therapy using rt-PA in patients diagnosed with acute ischemic stroke.