Analysis of genetic etiology and related factors in 1 065 women with spontaneous abortions / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic etiology and related factors in 1 065 women with spontaneous abortions.@*METHODS@#All patients have presented at the Center of Prenatal Diagnosis of Nanjing Drum Tower Hospital from January 2018 to December 2021. Chorionic villi and fetal skin samples were collected, and the genomic DNA was assayed by chromosomal microarray analysis (CMA). For 10 couples with recurrent spontaneous abortions but normal CMA results for abortive tissues, non-in vitro fertilization-embryo transfer (IVF-ET) pregnancies and no previous history of live births and no structural abnormalities of the uterus, peripheral venous blood samples were collected. Genomic DNA was subjected to trio-whole exome sequencing (trio-WES). Candidate variants were verified by Sanger sequencing and bioinformatics analysis. Multifactorial unconditional logistic regression analysis was carried out to analyze the factors that may affect chromosomal abnormality in spontaneous abortions, such as the age of the couple, number of previous spontaneous abortions, IVF-ET pregnancy and history of live birth. The incidence of chromosomal aneuploidies in spontaneous abortions during the first trimester was compared in young or advanced-aged patients by chi-square test for liner trend.@*RESULTS@#Among the 1 065 spontaneous abortion patients, 570 cases (53.5%) of chromosomal abnormalities were detected in spontaneous abortion tissues, which included 489 cases (45.9%) of chromosomal aneuploidies and 36 cases (3.4%) of pathogenic/likely pathogenic copy number variations (CNVs). Trio-WES results have revealed one homozygote variant and one compound heterozygote variants in two pedigrees, both of which were inherited from the parents. One likely pathogenic variant was detected in the patient from two pedigrees. Multifactorial unconditional Logistic regression analysis suggested that age of patient was an independent risk factor of chromosome abnormalities (OR = 1.122, 95%CI: 1.069-1.177, P < 0.001), the number of previous abortions and IVF-ET pregnancy were independent protective factors for chromosomal abnormalities (OR = 0.791, 0.648; 95%CI: 0.682-0.916, 0.500-0.840; P = 0.002, 0.001), whilst the age of husband and history of live birth were not (P > 0.05). The incidence of aneuploidies in the abortive tissues has decreased with the number of previous spontaneous abortions in young patients (χ² = 18.051, P < 0.001), but was not significantly correlated with the number of previous spontaneous abortions in advanced-aged patients with spontaneous abortions (P > 0.05).@*CONCLUSION@#Chromosomal aneuploidy is the main genetic factor for spontaneous abortion, though CNVs and genetic variants may also underlie its genetic etiology. The age of patients, number of previous abortions and IVF-ET pregnancy are closely associated with chromosome abnormalities in abortive tissues.

Follow-up of fetuses with de novo copy number variations of unknown significance detected by chromosomal microarray analysis / 中华医学遗传学杂志

OBJECTIVE@#To analyze the prognosis of fetuses identified with de novo variants of unknown significance (VOUS) by chromosome microarray analysis (CMA).@*METHODS@#A total of 6 826 fetuses who underwent prenatal CMA detection at the Prenatal Diagnosis Center of Drum Tower Hospital from July 2017 to December 2021 were selected as the study subjects. The results of prenatal diagnosis, and outcome of fetuses identified with VOUS of de novo origin were followed up.@*RESULTS@#Among the 6 826 fetuses, 506 have carried VOUS, of which 237 were detected for the parent-of-origin and 24 were found to be de novo. Among the latters, 20 were followed up for 4 to 24 months. Four couples had opted elective abortion, 4 had developed clinical phenotypes after birth, and 12 were normal.@*CONCLUSION@#Fetuses with VOUS should be continuously follow-up, in particular those carrying de novo VOUS, in order to clarify their clinical significance.

A multi-behavior recognition method for macaques based on improved SlowFast network / 生物医学工程学杂志

Macaque is a common animal model in drug safety assessment. Its behavior reflects its health condition before and after drug administration, which can effectively reveal the side effects of drugs. At present, researchers usually rely on artificial methods to observe the behavior of macaque, which cannot achieve uninterrupted 24-hour monitoring. Therefore, it is urgent to develop a system to realize 24-hour observation and recognition of macaque behavior. In order to solve this problem, this paper constructs a video dataset containing nine kinds of macaque behaviors (MBVD-9), and proposes a network called Transformer-augmented SlowFast for macaque behavior recognition (TAS-MBR) based on this dataset. Specifically, the TAS-MBR network converts the red, green and blue (RGB) color mode frame input by its fast branches into residual frames on the basis of SlowFast network and introduces the Transformer module after the convolution operation to obtain sports information more effectively. The results show that the average classification accuracy of TAS-MBR network for macaque behavior is 94.53%, which is significantly improved compared with the original SlowFast network, proving the effectiveness and superiority of the proposed method in macaque behavior recognition. This work provides a new idea for the continuous observation and recognition of the behavior of macaque, and lays the technical foundation for the calculation of monkey behaviors before and after medication in drug safety evaluation.

Value of chromosomal microarray analysis for the diagnosis of fetuses with anomalies of central nervous system / 中华医学遗传学杂志

OBJECTIVE@#To assess the value of chromosomal microarray analysis (CMA) for the diagnosis of fetuses with anomalies of the central nervous system (CNS) and summarize the outcome of the pregnancies and follow-up.@*METHODS@#A total of 636 fetuses from June 2014 to December 2020 who were referred to the Prenatal Diagnosis Center of Nanjing Drum Tower Hospital due to abnormal CNS prompted by ultrasound were selected as the research subjects. Based on the ultrasound findings, the fetuses were divided into ventricular dilatation group (n = 441), choroid plexus cyst group (n = 41), enlarged posterior fossa group (n = 42), holoprosencephaly group (n = 15), corpus callosum hypoplasia group (n = 22), and other anomaly group (n = 75). Meanwhile, they were also divided into isolated (n = 504) and non-isolated (n = 132) groups based on the presence of additional abnormalities. Prenatal samples (amniotic fluid/chorionic villi/umbilical cord blood) or abortus tissue were collected for the extraction of genomic DNA and CMA assay. Outcome of the pregnancies and postnatal follow-up were summarized and subjected to statistical analysis.@*RESULTS@#In total 636 fetuses with CNS anomalies (including 89 abortus tissues) were included, and 547 cases were followed up. The overall detection rate of CMA was 11.48% (73/636). The detection rates for the holoprosencephaly group, ACC group, choroid plexus cyst group, enlarged posterior fossa group, ventricular dilatation group and other anomaly group were 80% (12/15), 31.82% (7/22), 19.51% (8/41), 14.29% (6/42), 7.48% (33/441) and 9.33% (7/75), respectively. Compared with the isolated CNS anomaly group, the detection rate for the non-isolated CNS anomaly group was significantly higher (6.35% vs. 31.06%) (32/504 vs. 41/132) (χ² = 62.867, P < 0.001). Follow up showed that, for 52 fetuses with abnormal CMA results, 51 couples have opted induced labor, whilst 1 was delivered at full term with normal growth and development. Of the 434 fetuses with normal CMA results, 377 were delivered at full term (6 had developmental delay), and 57 couples had opted induced labor. The rate of adverse pregnancy outcome for non-isolated CNS abnormal fetuses was significantly higher than that of isolated CNS abnormal fetuses (26.56% vs. 10.54%) (17/64 vs. 39/370) (χ² = 12.463, P < 0.001).@*CONCLUSION@#Fetuses with CNS anomaly should be tested with CMA to determine the genetic cause. Most fetuses with negative CMA result have a good prognosis, but there is still a possibility for a abnormal neurological phenotype. Fetuses with CNS abnormalities in conjunct with other structural abnormalities are at increased risk for adverse pregnancy outcomes.

Focusing on prenatal genetic counseling and proper option of genetic testing methods / 中华围产医学杂志

More and more new technologies are being applied to prenatal diagnosis as the development of genetic testing technology advances. Pedigree analysis and phenotype recognition are the foundation of prenatal genetic counseling and diagnosis. In addition, fully understanding the advantages and disadvantages of different genetic testing techniques, developing a rationale, standardized and sequential testing strategy for the affected family, and analyzing the underlying genetic etiology and prognosis are critical for prenatal diagnosis and achieving the goal of birth defect prevention.

Chromosomal microarray analysis in prenatal diagnosis of women with isolated adverse pregnancy history / 中华围产医学杂志

Objective:To investigate the abnormal results of chromosomal microarray analysis (CMA) in the subsequent pregnancy of women with adverse pregnancy history, and explore the applicability of CMA in women with different genetic etiology.Methods:Out of 5 563 pregnant women who received CMA test in Nanjing Drum Tower Hospital during June 2014 and July 2020, 169 cases that underwent prenatal diagnosis due to isolated adverse pregnancy history were retrospectively collected in this study. All the participants were divided into three groups based on the etiology type of probands, genetic origin and expected CMA outcome: high-risk group ( n=19, including 11 cases with inherited pathogenic copy number variations and eight cases with inherited chromosomal abnormalities), low-risk group ( n=113, including six cases with negative whole exome sequencing and/or CMA findings, 31 cases with confirmed monogenic disease, 47 cases with de novo pathogenic copy number variations and 29 cases with de novo chromosomal abnormalities), and unknown risk group ( n=40, none of the cases underwent genetic testing). Descriptive statistical analysis was used to summarize the abnormal detection of each group. Results:There were 169 mothers with 172 fetuses finally enrolled, including two twins and one woman with two singleton pregnancies. A total of nine cases of abnormal fetuses were detected by CMA, accounting for 5.2% (9/172). Among them, eight were in the high-risk group, which were all caused by parental abnormalities, and one case in the low-risk group was detected with a de novo 22q11.22q11.23 microduplication, which was arr[GRCh37]22q11.22q11.23(22,997,928-25,002,659)×3. No abnormality was detected in the 40 patients of unknown risk group. Conclusions:Clarifying the etiology of isolated adverse pregnancy history is crucial to the rational application of CMA. Monogenic disease, unknown cause or negative finding of CMA in probands may not be an indication for prenatal diagnosis of CMA.

Genetic analysis and prenatal diagnosis of a pedigree with oculo-facio-cardio-dental syndrome: a case report and literature review / 中华围产医学杂志

Objective:To analyze the clinical phenotypes and prenatal diagnosis of a pedigree with oculo-facio-cardio-dental (OFCD) syndrome.Methods:A pregnant woman at 17 gestational weeks was admitted to the Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School in 2017 for genetic counseling. Genetic tests as performed for the proband (the pregnant woman), her husband, and the induced fetus of last pregnancy genetic test and the detected variants were analyzed and verified by chromosomal microarray analysis (CMA), multiplex ligation-dependent probe amplification (MLPA) and quantitative real time-polymerase chain reaction (Q-PCR). The detection platform established by MLPA and Q-PCR technology was used to perform prenatal diagnosis of the present pregnancy. Other family members were screened for BCOR gene mutation. Related mutation types were retrieved from ClinVar database with term of " BCOR", and related literature from CNKI and PubMed with terms of "OFCD syndrome", " BCOR gene", and "oculo facio cardiac dental syndrome" to summarize the clinical manifestations, mutation type and pathogenesis of this disease. Results:The proband has congenital cataracts, long face, congenital atrial septal defect, and severe dental malformations, which were consistent with the clinical features of OFCD syndrome. WES suggested that the proband and her induced fetus were suspected of having a large submicroscopic deletion of the exons of BCOR gene, which was confirmed by CMA, MLPA and Q-PCR, with a 105 kb deletion containing BCOR exons 1-15. The amniotic fluid genetic analysis of the present pregnancy showed that the fetus has a normal female karyotype, and did not carry the same BCOR gene copy number abnormality as the proband. The child grew and normally developed without any characteristic manifestations of OFCD syndrome during follow-up. Other families of the proband did not show clinical features of OFCD syndrone, and no BCOR gene copy number abnormality was detected. A total of 35 cases of BCOR gene mutation types related to OFCD syndrome were retrieved from ClinVar database. The data analysis revealed that the differences in clinical manifestations between Lenz microphthalmos syndrome and OFCD syndrome were mainly caused by different mutation types of BCOR gene. Among the 90 retrieved cases of OFCD syndrome obtained through literature, only one case was reported in China. Analysis of these 90 cases showed that the characteristic manifestations of OFCD syndrome, involving the eye, face, heart, teeth, and skeletal system. OFCD syndrome were confirmed in the proband and her induced fetus according to the clinical manifestation and the mutation type of BCOR gene. Conclusions:The clinical manifestations of OFCD syndrome are complicated, caused by various mutation types of BCOR. Systematic molecular genetic technology can be effectively applied for gene and prenatal diagnosis of OFCD syndrome.

Effects of sorafenib on hypoxia inducible factor-1 and vascular endothelial growth factor levels and recurrence in patients with intrahepatic cholangiocarcinoma with microvascular invasion / 中国基层医药

Objective:To investigate the effects of sorafenib on hypoxia inducible factor-1 (HIF-1) and vascular endothelial growth factor (VEGF) levels and recurrence in patients with intrahepatic cholangiocarcinoma with microvascular invasion.Methods:Ninety-two patients with intrahepatic cholangiocarcinoma who received treatment in Yiwu Central Hospital between November 2013 and November 2019 were included in this study. They were randomly assigned to undergo either conventional basic treatment (control group, n = 46) or conventional basic treatment and sorafenib treatment (study group, n = 46). Clinical efficacy, the incidence of adverse reactions and recurrence rate were compared between the two groups. Before and after treatment, HIF-1, alpha fetoprotein (AFP) and VEGF levels were also compared between the two groups. Results:After treatment, total effective rate in the study group was significantly higher than that in the control group [63.04% (29 /46) vs. 28.26% (13/46), χ2 = 11.215, P < 0.05]. After treatment, HIF-1, AFP and VEGF levels in each group were significantly lower than those before treatment (all P > 0.05). After treatment, HIF-1 [(165.23 ± 39.67) pg/mL], AFP [(109.16 ± 67.31) ng/mL] and VEGF [(297.28 ± 42.41) pg/mL] levels in the study group were significantly lower than those in the control group [(205.56 ± 40.23) pg/mL, (235.17 ± 106.41) ng/mL, (365.16 ± 40.91) pg/mL, t = 4.841, 6.788, 7.813, all P < 0.05]. There was no significant difference in the incidence of adverse reactions between the two groups ( P > 0.05). Six-month follow-up revealed that the incidence of recurrence in the study group was significantly lower than that in the control group ( χ2 = 4.792, P < 0.05). Conclusion:Sorafenib can reduce the HIF-1, AFP and VEGF levels in patients with intrahepatic cholangiocarcinoma with microvascular invasion, improve the clinical efficacy, decrease the incidence of recurrence, but cannot increase the incidence of adverse reactions.

Analysis of PHEX gene variant and prenatal diagnosis for a Chinese pedigree affected with X-linked hypophosphatemia / 中华医学遗传学杂志

OBJECTIVE@#To detect pathological variant in a Chinese pedigree affected with X-linked hypophosphatemia (XLH).@*METHODS@#Whole-exome sequencing was carried out to screen genetic variants in the proband and her parents. Candidate variant of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) was verified by Sanger sequencing of all members of the pedigree and the 100 healthy controls. Prenatal diagnosis was carried out on chorionic villi sample derived from the fetus of the proband.@*RESULTS@#A c.1256G>A (p. Gly419Glu) variant was identified in the PHEX gene of the proband and all other patients from this pedigree. The same variant was not found among healthy members from this pedigree and the 100 healthy controls. Prenatal diagnosis suggested that the fetus also carried the c.1256G>A (p. Gly419Glu) variant.@*CONCLUSION@#The c.1256G>A (p. Gly419Glu) variant of the PHEX gene probably underlay the pathogenesis of XLH in this family. Discovery of the novel variant has enriched the mutational spectrum of the PHEX gene.

Analysis of PHEX gene variant and prenatal diagnosis for a Chinese pedigree affected with X-linked hypophosphatemia / 中华医学遗传学杂志

OBJECTIVE@#To detect pathological variant in a Chinese pedigree affected with X-linked hypophosphatemia (XLH).@*METHODS@#Whole-exome sequencing was carried out to screen genetic variants in the proband and her parents. Candidate variant of the phosphate regulating gene with homologies to endopeptidases on the X chromosome (PHEX) was verified by Sanger sequencing of all members of the pedigree and the 100 healthy controls. Prenatal diagnosis was carried out on chorionic villi sample derived from the fetus of the proband.@*RESULTS@#A c.1256G>A (p. Gly419Glu) variant was identified in the PHEX gene of the proband and all other patients from this pedigree. The same variant was not found among healthy members from this pedigree and the 100 healthy controls. Prenatal diagnosis suggested that the fetus also carried the c.1256G>A (p. Gly419Glu) variant.@*CONCLUSION@#The c.1256G>A (p. Gly419Glu) variant of the PHEX gene probably underlay the pathogenesis of XLH in this family. Discovery of the novel variant has enriched the mutational spectrum of the PHEX gene.

Analysis of related phenotype of prenatal cases with copy number variations in various region of 22q11.2 / 中华医学遗传学杂志

OBJECTIVE@#To analyze the prenatal ultrasound phenotypes of copy number variations (CNVs) in different regions of 22q11.2, their parental original, and pregnancy outcome.@*METHODS@#Prenatal phenotypes of 25 cases with CNVs of the 22q11.2 region detected by chromosomal microarray analysis (CMA) was reviewed, which including There were 13 deletions and 12 duplications. Multiplex ligation-dependent probe amplification(MLPA) was carried out to determine their parental origin. All cases were followed up for their pregnancy outcome and postnatal growth.@*RESULTS@#Among the 25 cases, the ultrasound phenotypes of those involving the TBX1 gene were mostly cardiovascular system abnormalities, the ultrasound phenotypes of cases involving CRKL gene are mostly polycystic renal dysplasia. The ultrasound phenotypes of CNVs in the distal region (involving the SMARCB1 gene) are nervous system abnormalities. 12 cases (48%) of CNVs were de novo in origin. Five cases were lost during follow-up,12 had opted to terminate the pregnancy, 8 fetuses were born,7 with normal growth and development, 1 case with CNV in A-D region was abnormal.Prenatal ultrasound showed abnormalities in the cardiovascular system consistent with postnatal ultrasound, in addition with dysphagia and growth retardation.@*CONCLUSION@#Prenatal phenotypes of the 22q11.2 region CNVs are diverse, which may be related to gene function. NT thickening may be used as an early ultrasound finding of proximal 22q11.2 CNV. More research is still required to delineate the nature of CNVs and gene function, so as to facilitate genetic counseling.

Genetic study of a pedigree affected with oculodentodigital dysplasia / 中华医学遗传学杂志

Objective@#To explore the genetic basis of a pedigree affected with oculodentodigital dysplasia.@*Methods@#Genomic DNA was extracted from peripheral blood or amniotic fluid samples derived from the pedigree. Exon 2 of the GJA1 gene was amplified for sequencing.@*Results@#Two pedigree members were found to carry heterozygous missense variation of the GJA1 gene, c. 221A>C (p.H74P).@*Conclusion@#The missense c. 221A>C variation of the GJA1 gene probably underlies the oculodentodigital dysplasia in this pedigree.

Application of chromosomal microarray analysis in prenatal diagnosis of fetuses with increased nuchal translucency / 中华医学遗传学杂志

Objective@#To determine the frequency of chromosomal abnormalities and outcome of pregnancy for fetuses with increased nuchal translucency (NT).@*Methods@#Between July 2014 and February 2018, 247 fetuses with increased NT (>95th centile)were analyzed by chromosome microarray analysis (CMA). The fetuses were divided into ones with isolated increased NT(168 cases), increased NT with cystic hygroma(20 cases), increased NT with edema(12 cases) or increased NT with other abnormalities(47 cases). All couples were followed up by telephone calls.@*Results@#The rate of chromosomal abnormalities was 31.6% (78/247), which included 66 cases with chromosomal aneuploidies and 12 with copy number variants(CNVs). CNVs accounted for 31.4% (11/35) of total abnormalities among fetuses with isolated increased NT, whilst only 2.3% (1/43)of the total abnormalities among fetuses with non-isolated increased NT. Three fetuses with a normal CMA result had mental and physical retardation. Two of them were diagnosed with single gene disorders by whole exome sequencing.@*Conclusion@#CMA can detect more chromosomal microdeletion/microduplications among fetuses with isolated increased NT. Furthermore, fetuses with increased NT and anegative CMA result during pregnancy cannot exclude all adverse outcomes.

Effects of Glycyrrhizic Acid on Pharmacokinetics of Nifedipine in Rats / 中国药房

OBJECTIVE： To study the effects of glycyrrhizic acid on the pharmacokinetics of nifedipine in rats. METHODS： Rats were randomly divided into experimental group and control group， with 10 rats in each group. Experimental group was given glycyrrhizic acid 5 mg/kg and control group was given 0.5％ CMC-Na （sodium carboxymethylcellulose） solution， once a day， for 14 consecutive days. On 14th day after 30 min of intragastric administration， both groups were given nifedipine 3 mg/kg intragastrically. Blood samples 0.5 mL were collected from intraocular vein plexus before and at 0.25， 0.5， 0.75， 1， 1.5， 2， 3， 4， 6， 8， 12 and 24 h after intragastric administration. The concentration of nifedipine was determined by HPLC using diazepam as internal standard. The determination was performed on ODS-C18 column with mobile phase consisted of methanol-water （62 ∶ 38，     V/V，pH adjusted to 4.5 with acetic acid） at the flow rate of 1.0 mL/min. The column temperature was 30 ℃. The detection wavelength was set at 238 nm， and sample size was 20 μL. The pharmacokinetic parameters were calculated with Winonlin 6.0 software， and statistical analysis was performed by t-test. RESULTS： The main pharmacokinetic parameters of the experimental group and the control group were as follows as tmax was （1.40±0.15）， （1.50±0.01） h； cmax was （0.15±0.03）， （0.29±0.09）      mg/L； t1/2 was （4.70±1.17）， （5.20±1.38） h； AUC0-24 h were （1.00±0.10）， （1.89±0.37） mg·h/L； AUC0-∞ was （1.00±0.16）， （1.98±0.32） mg·h/L； MRT was （6.76±0.64）， （6.60±1.36） h， respectively. Compared with control group， cmax， AUC0-24 h and AUC0-∞ of nifedipine were decreased significantly in experimental group， with statistical significance （P＜0.05）. CONCLUSIONS： Glycyrrhizic acid can reduce the bioavailability of nifedipine in rats. It is suggested that the dosage of nifedipine should be increased in order to achieve effective blood concentration.

Genetic study of a pedigree affected with oculodentodigital dysplasia / 中华医学遗传学杂志

OBJECTIVE@#To explore the genetic basis of a pedigree affected with oculodentodigital dysplasia.@*METHODS@#Genomic DNA was extracted from peripheral blood or amniotic fluid samples derived from the pedigree. Exon 2 of the GJA1 gene was amplified for sequencing.@*RESULTS@#Two pedigree members were found to carry heterozygous missense variation of the GJA1 gene, c.221A>C (p.H74P).@*CONCLUSION@#The missense c.221A>C variation of the GJA1 gene probably underlies the oculodentodigital dysplasia in this pedigree.

Application of chromosomal microarray analysis in prenatal diagnosis of fetuses with increased nuchal translucency / 中华医学遗传学杂志

OBJECTIVE@#To determine the frequency of chromosomal abnormalities and outcome of pregnancy for fetuses with increased nuchal translucency (NT).@*METHODS@#Between July 2014 and February 2018, 247 fetuses with increased NT (>95th centile)were analyzed by chromosome microarray analysis (CMA). The fetuses were divided into ones with isolated increased NT (168 cases), increased NT with cystic hygroma (20 cases), increased NT with edema (12 cases) or increased NT with other abnormalities (47 cases). All couples were followed up by telephone calls.@*RESULTS@#The rate of chromosomal abnormalities was 31.6% (78/247), which included 66 cases with chromosomal aneuploidies and 12 with copy number variants (CNVs). CNVs accounted for 31.4% (11/35) of total abnormalities among fetuses with isolated increased NT, whilst only 2.3% (1/43) of the total abnormalities among fetuses with non-isolated increased NT. Three fetuses with a normal CMA result had mental and physical retardation. Two of them were diagnosed with single gene disorders by whole exome sequencing.@*CONCLUSION@#CMA can detect more chromosomal microdeletion/microduplications among fetuses with isolated increased NT. Furthermore, fetuses with increased NT and anegative CMA result during pregnancy cannot exclude all adverse outcomes.

Mutation analysis for a methylmalonic acidemia pedigree without proband by high-throughput sequencing / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To apply high-throughput sequencing for the detection of potential mutation in a methylmalonic academia pedigree for which no proband was available.</p><p><b>METHODS</b>For a couple who had previously given birth to an affected child, 14 genes were re-sequenced by high-throughput sequencing. Suspected mutations were validated by Sanger sequencing. Specific mutations were tested for amniotic fluid sample from the fetus.</p><p><b>RESULTS</b>High-throughput sequencing suggested that the husband has carried a heterozygous mutation of the MUT gene (Exon 3: c.729_730insTT; p.Asp244Leufs*39), while the wife also carried a heterozygous mutation of the MUT gene (Exon 5: c.914T>C; p.Leu305Ser). Both mutations were confirmed by Sanger sequencing. Testing of amniotic sample suggested that the fetus has carried neither mutation. Follow-up has found no sign of methylmalonic academia in the neonate.</p><p><b>CONCLUSION</b>High-throughput sequencing is a sensitive method to screen a bunch of genes in a single test. For autosomal recessive diseases, when no proband is available, carrier testing for both parents with high-throughput sequencing can provide an alternative approach, though great caution should be taken in the setting of prenatal diagnosis.</p>

Mutation analysis in a pedigree with oculocutaneous albinism / 中华皮肤科杂志

Objective To investigate gene mutations in a pedigree with oculocutaneous albinism by using targeted next-generation sequencing technology.Methods Clinical data were collected from a pedigree with oculocutaneous albinism.Genomic DNA was extracted from peripheral blood cells of the proband and his parents.High-throughput sequencing technology was used for sequence analysis of coding regions in exons of 29 genes including TYR,OCA2,TYRP1 and SLC45A2 in the proband to find potential pathogenic gene mutations.Sanger sequencing was conducted to detect the corresponding genetic loci in the parents.Results Two heterozygous mutations were identified in the TYR gene of the proband,including a novel mutation c.534G ＞ C (p.Trp178Cys) and a known mutation c.1147G ＞ A (p.Asp383Asn).The detection of the TYR gene mutations in the parents of the proband showed that the c.534G ＞ C and c.1147G ＞ A mutations in the proband were inherited from his father and mother respectively.Conclusion A novel pathogenic mutation c.534G ＞ C in the TYR gene is identified in the pedigree with oculocutaneous albinism by using targeted next-generation sequencing technology.

Chromosome microarray analysis of four fetuses with abnormal karyotypes / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To carry out chromosomal microarray analysis (CMA) on four fetuses with abnormal karyotypes.</p><p><b>METHODS</b>Amniotic fluid samples were obtained and subjected to routine G-banded karyotyping analysis. CMA was applied for cultured amniocytes to determine alterations of gene dosage and chromosomal breakpoints.</p><p><b>RESULTS</b>Abnormal karyotypes were found in the parents of 3 fetuses. Parental karyotypes of the remaining fetus were normal. Imbalance chromosome rearrangements were revealed by CMA in all 4 cases.</p><p><b>CONCLUSION</b>CMA is an effective tool for the evaluation of clinical significance and delineation of the breakpoints involved in complex chromosomal rearrangements.</p>

Prenatal diagnosis and follow-up of a case with Lowe syndrome caused by interstitial deletion of Xq25-26 / 中华医学遗传学杂志

<p><b>OBJECTIVE</b>To report on a sporadic case of Lowe syndrome diagnosed prenatally with ultrasound examination and genetic testing.</p><p><b>METHODS</b>Detailed sonographic fetal screening was performed by an experienced sonographer at 32 weeks of gestation. Fetal cranial magnetic resonance imaging (MRI) was applied to detect potential brain abnormality. Chromosomal microarray analysis (CMA) was conducted on amniotic fluid sample from the fetus and peripheral blood sample from the mother.</p><p><b>RESULTS</b>Congenital cataract and enlarged posterior fossa were detected by fetal ultrasound screening. Fetal cranial MRI found hypoplasia of the gyrus. CMA revealed that the fetus has carried a 633 kb deletion at Xq25-26.1 which encompassed the OCRL gene. The mother was a carrier of the same deletion. Clinical examination after birth confirmed that the neonate was affected with Lowe syndrome in addition with an atrial septal defect.</p><p><b>CONCLUSION</b>Prenatal diagnosis of Lowe syndrome without a family history largely depends on fetal imaging. Should cataract be found by ultrasound screening, fetal MRI may be considered to rule out central nervous system anomalies. CMA assay should also be considered to facilitate the diagnosis.</p>