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OBJECTIVE@#To explore the genetic basis for a couple with recurrent conceptions of fetus with abnormal longbones, and another couple with a history of omphalocele.@*METHODS@#Genomic DNA was extracted from the peripheral blood samples from both couples. All exons and flanking regions were analyzed with next generation sequencing. Candidate variants were verified by Sanger sequencing.@*RESULTS@#Couple one was found to be heterozygous for, a c.997+1G>T splice-site variant and a missence c.871G>A(p.Glu291Lys) variant of the ALPL gene. Both variants were predicted to be pathogenic and may result in reduced function or loss of alkaline phosphatase. For couple two, the wife was found to harbor a novel c.637_652 delins CCC variant of the CDKN1C gene. This deletion-insertion variant resulted in frame-shift and loss of function (p.Ala213Profs*55) of the CDKN1C protein. Maternally inherited CDKN1C LOF variant has been found to underlie Beckwith-Wiedemann syndrome (BWS), which may manifest as omphalocele.@*CONCLUSION@#Dispite the lack the direct proof from the lost fetuses, the variants of ALPL and CDKN1C genes can explain the recurrence of fetal malformations for both couples.
Subject(s)
Humans , Beckwith-Wiedemann Syndrome , Fetus , MutationABSTRACT
OBJECTIVE@#To explore the genetic basis for a consanguineous pedigree affected with inherited coagulation factor V deficiency.@*METHODS@#Genomic DNA was extracted from peripheral blood samples from the pedigree and subjected to next generation sequencing for screening variants of the F5 gene. Suspected pathogenic variant was verified by using Sanger sequencing. Pathogenicity of the variant was evaluated according to ACMG guidelines.@*RESULTS@#A homozygous frameshifting variant, c.4096delC (p.Leu1366Phefs*3), was identified in the F5 gene in the proband, which was confirmed to be derived from her consanguineous parents. This variant was absent in all databases including 10 000 in-house Chinese exome sequences. Based on the ACMG guidelines, the c.4096delC was predicted to be a pathogenic variant.@*CONCLUSION@#A novel pathogenic variant has been identified in the F5 gene in a consanguineous pedigree with inherited coagulation factor V deficiency, which has enriched the spectrum of F5 gene variants.
Subject(s)
Female , Humans , Consanguinity , Factor V , Genetics , Factor V Deficiency , Genetics , Genetic Variation , PedigreeABSTRACT
OBJECTIVE@#To emphasize the clinical significance of copy number variations (CNVs) detection by describing a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis.@*METHODS@#A girl with obesity and short stature was diagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. Considering the discrepancy of her karyotype with her phenotype, genomic CNVs was detected by next-generation sequencing and the result was verified by quantitative PCR (qPCR).@*RESULTS@#A microduplication of 16p11.2: 29 642 339-29 775 631 (133.292 kb) was detected. qPCR assay for QPRT and SPN located in the duplicated region confirmed the finding of CNVs assay. Meanwhile, her parents did not present similar duplication in 16p11.2.@*CONCLUSION@#The 16p11.2 microduplication was a novel genomic structural variation in the girl, though it may not be associated with her clinical manifestations. Chromosomal microarray or next-generation sequencing-based CNVs detection can accurately determine the origin of small supernumerary marker chromosome and reduce the chance of misdiagnosis.
Subject(s)
Female , Humans , Chromosome Banding , Chromosomes, Human, Pair 21 , Genetics , DNA Copy Number Variations , Diagnostic Errors , Down Syndrome , Karyotyping , Trisomy , DiagnosisABSTRACT
Objective@#To emphasize the clinical significance of copy number variations (CNVs) detection by describing a case misdiagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis.@*Methods@#A girl with obesity and short stature was diagnosed as trisomy 21 syndrome by G-banded chromosomal karyotype analysis. Considering the discrepancy of her karyotype with her phenotype, genomic CNVs was detected by next-generation sequencing and the result was verified by quantitative PCR (qPCR).@*Results@#A microduplication of 16p11.2: 29 642 339-29 775 631 (133.292 kb) was detected. qPCR assay for QPRT and SPN located in the duplicated region confirmed the finding of CNVs assay. Meanwhile, her parents did not present similar duplication in 16p11.2.@*Conclusion@#The 16p11.2 microduplication was a novel genomic structural variation in the girl, though it may not be associated with her clinical manifestations. Chromosomal microarray or next-generation sequencing-based CNVs detection can accurately determine the origin of small supernumerary marker chromosome and reduce the chance of misdiagnosis.
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Objective: In comparison with thrombus aspiration, to study the safety and effcacy of precise intracoronary retrograde thrombolysis during primary percutaneous coronary intervention (PCI) in patients with acute ST-segment elevation myocardial infarction (STEMI). Methods: A total of 123 consecutive patients with acute STEMI received primary PCI in our hospital from 2014-01 to 2015-12 were enrolled.The patients were randomly divided into 2 groups: RT group, the patients received precise intracoronary retrograde thrombolysis (RT),n=60 and TA group, the patients received thrombus aspiration (TA),n=63, among them, 3 patients with failed TA were excluded. Primary end points included occurrence rates of no-lfow after PCI and ST-segment resolution (STR)≥50% at (60-90) min after PCI; primary safety end points included occurrence rates of in-hospital stroke and TIMI-hemorrhage events. Results:①Compared with TA group, RT group showed decreased no-lfow rate after PCI (1.7% vs 15.0%),P=0.008 and increased rate of STR≥50% after PCI (65.0% vs 45.0%),P=0.028, improved LVEF by echocardiography (50.7±8.6) % vs (46.7±8.3)%,P=0.011. The in-hospital MACE occurrence rate was similar between 2 groups,P>0.05.②No in-hospital stroke or TIMI-hemorrhage events occurred in neither group. Conclusion: Intracoronary retrograde precise thrombolysis had the similar safety to thrombus aspiration during primary PCI in patients with acute STEMI, it may reduce no-relfow rate and improve left ventricular function after PCI.
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This study examined the current changes of human ether-a-go-go-related gene (hERG) mutation derived from a LQT2 Chinese family with a highly penetrating phenotype. Mutation was identified and site-directed mutagenesis was performed to induce the mutation in wild-type (WT) hERG. WT hERG and mutated V535M were cloned and transiently expressed in HEK293 cells. At the 48th and 72nd h after transfection, membrane currents were recorded using whole cell patch-clamp procedures. An A>G transition at 1605 resulting in replacement of V535M was identified. Compared to WT, V535M mutation significantly decreased tail currents of hERG. At test potential of -40 mV after depolarizing at +50 mV, tail current densities were 83.35±7.06 pA/pF in WT and 50.38±7.74 pA/pF in V535M respectively (n=20, P<0.01). Gating kinetics of hERG revealed that V (1/2) of steady-state inactivation shifted to negative potential in the mutant (V (1/2,V535M): -61.81±1.7 mV vs. V (1/2, WT): -43.1±0.71 mV). The time constant of recovery from inactivation was markedly prolonged in the mutant compared to WT among test potentials. V535M hERG mutation demonstrated markedly decreased tail current densities, which suggests that V535M is a new loss-of-function mutation of hERG channel responsible for LQT2.
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Objective To investigate the relationship of blood pressure circadian rhythm with myocardial hypertrophy and the changes of autonomic nerve function in patients with essential hypertension (EH). Methods Eighty-two female patients with essential hypertension (EH) underwent 24-hours ambulatory blood pressure monitorings (ABPM), dynamic electrocardiogram (Holter) and echocardiography examination. Patients were classified into non-dipping group (n=40) and dipping group (n=42) according to the result of ABPM. Left ventricular mass index (LVMI), heart rate variability (HRV) in time domain (including SDNN, SDANN, rMSSD, PNN50) and heart rate turbulence (HRT) parameters (including turbulence onset [TO] and turbulence slope [TS]) were measured. Results Compared with those in dipping group, patients in non-dipping group have higher incidence of LVH (19.0% vs 52.5%, P<0.01), greater mean LVMI (112.39±12.79 g/m2 vs 121.98±13.35 g/m2, P<0.01), decreased PNN50 and rMSSD. TS value was decreased while TO was increased in non-dipping group compared with those in dipping group (both P <0.01); patients with LVH showed decreased TS and increased TO, compared with those without LVH. Conclusion In female patients with EH, non-dipping blood pressure circadian is associated with higher incidence of LVH. The HRV and HRT were more remarkably blunted in non-dipping patients, as well as those with LVH.
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Objective To determine whether sleep-disordered breathing (SDB) may lead to nocturnal myocardial ischemia and whether the severity of this ischemia may be relieved by nasal continuous positive airway pressure (CPAP). Methods Overnight polysomnogram examination and simultaneous 3-channel Holter monitoring were performed on 76 patients with moderate to severe SDB and no history of coronary heart disease. All the cases were treated with CPAP for one night. ST depression was defined as a ST segment decrease of more than 1 mm from baseline and lasting 1 min or more. The total duration (minutes) of ST depression was indexed to the total sleep time (minutes per hour of sleep). Results Twenty-eight patients (37%) showed ST segment depression during their sleep. Before CPAP treatment, the respiratory disturbance index (RDI) and arousal index were significantly higher during periods of ST depression than when ST segments were isoelectric, whereas no significant difference was found in blood oxygen saturation (SaO2). After the CPAP treatment of patients with ST depression, the duration of ST depression was significantly reduced from 36.8±18.9 to 11.4±13.2 min/h (P＜0.05). ST depression-related indexes, including RDI, arousal index and the percentage of sleep time spent at SaO2 below 90% (TS90/ TST), were all significantly decreased, with RDI from 63.4±23.8 to 8.1±6.6 /h, arousal index from 51.2±18.9 to 9.6±5.4 /h, and TS90/ TST from 50.6±21.4 to 12.9±14.7% (P＜0.05). Conclusion ST-segment depression is rather common in patients with moderate to severe SDB, and CPAP treatment can significantly reduce the duration of ST depression. ST depression in these patients may reflect the myocardial ischemia that really exists and the non-ischemic changes associated with recurrent SDB.