Aims:Multiple genes and environmental factors are known to be involved in congenital heart disease(CHD),but epigenetic variation has received little attention.Monozygotic(MZ)twins with CHD provide a unique model for e...Aims:Multiple genes and environmental factors are known to be involved in congenital heart disease(CHD),but epigenetic variation has received little attention.Monozygotic(MZ)twins with CHD provide a unique model for exploring this phenomenon.In order to investigate the potential role of Deoxyribonucleic Acid(DNA)methyla-tion in CHD pathogenesis,the present study examined DNA methylation variation in MZ twins discordant for CHD,especially ventricular septal defect(VSD).Methods and Results:Using genome-wide DNA methylation profiles,we identified 4004 differentially methylated regions(DMRs)in 18 MZ twin pairs discordant for CHD,and 2826 genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed a list of CHD-associated pathways.To further investigate the role of DNA methylation in VSD,data from 7 pairs of MZ twins with VSD were analyzed.We identified 1614 DMRs corresponding to 1443 genes associated with arrhythmogenic right ventricular cardiomyopathy,cyclic guanosine monopho-sphate-protein kinase G(cGMP-PKG)signaling pathway by KEGG analysis,and cell-cell adhesion,calcium ion transmembrane transport by GO analysis.A proportion of DMR-associated genes were involved in calcium signaling pathways.The methylation changes of calcium signaling genes might be related to VSD pathogenesis.Conclusion:CHD is associated with differential DNA methylation in MZ twins.CHD may be etiologically linked to DNA methylation,and methylation of calcium signaling genes may be involved in the development of VSD.展开更多
We are reporting a case of monozygotic twinning after donor egg intracytoplasmic sperm injection (ICSI). A 34-year-old lady presented to our centre with primary infertility due to severe endometriosis and low egg rese...We are reporting a case of monozygotic twinning after donor egg intracytoplasmic sperm injection (ICSI). A 34-year-old lady presented to our centre with primary infertility due to severe endometriosis and low egg reserve. ICSI with donor eggs was planned. A 24 years old voluntary oocyte donor was investigated and stimulated under antagonist protocol. Total 21 eggs and all in metaphaseⅡwere retrieved. These eggs were injected with the patient's husband sperms by ICSI. Patient's endometrial lining was prepared under hormonal replacement therapy protocol. Two expanded blastocysts were transferred on day 5 of progesterone. Beta human chorionic gonadotropin was positive after 10 days. The first antenatal scan at 6 weeks could pick up only two sacs indicating twin conception. Repeat scan at 12 weeks revealed tri-amniotic triplet conception with two foetuses sharing the same placenta (triamniotic pregnancy with monochorionic twins). The patient was counselled about risks associated with triplet conception and was advised of embryo reduction. Two mono chorionic twins were reduced under ultrasonography guidance. Single pregnancy continued till 21 weeks after which the patient miscarried spontaneously. It is difficult to identify the subset of patients at risk for monozygotic twinning;hence, all patients should be counselled about possibility of monozygotic twinning while deciding the number of embryos to be transferred.展开更多
Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant ...Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.展开更多
Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important ro...Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations （SNVs） and somatic insertions and deletions （indels） of SCZ. Methods： One Chinese family with a monozygotic （MZ） twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. Results： One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. Conclusions： This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.展开更多
Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder characterized by the development of hamartomas in the brain, heart, skin, kidney, lung, retina, and so on. One fetus from family 1 had a cardi...Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder characterized by the development of hamartomas in the brain, heart, skin, kidney, lung, retina, and so on. One fetus from family 1 had a cardiac rhabdomyoma from 21 weeks and 6 days of gestational age, and developed multiple rhabdomyomas and tubers in the brain at 23 weeks and 5 days. The counter monozygotic twin fetus remained negative throughout the pregnancy according to imaging examination. A nonsense mutation inTSC2 (c.4762C>T, p.Gln1588*) was identified in both twins, but not in the mother. Family 2 was one pair of twin fetuses caused by a microdeletion of exon 30 withinTSC2 inherited from their apparently asymptomatic mother with mosaic status. The larger fetus was identified as having the first cardiac rhabdomyoma from 17 weeks and 4 days of gestational age. The smaller fetus developed multiple rhabdomyomas until 25 weeks and 6 days of gestational age. Both families terminated the pregnancy. Here, we provide intrauterine examples of clinical variability among monozygotic twins suffering from TSC.展开更多
Primary myelofibrosis （PMF） is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected i...Primary myelofibrosis （PMF） is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected in children, suggesting a difference in the pathogenesis of childhood PMF. In this study, we investigated the response to drug treatment of a monozygotic twin pair with typical childhood PMF. The twin exhibited different clinical outcomes despite following展开更多
Objectives To study the incidence and potential causes of monozygotic twins after in vitro fertilization and embryo transfer （IVF-ET）. Methods A retrospective study was performed on women carrying monozygotic twins ...Objectives To study the incidence and potential causes of monozygotic twins after in vitro fertilization and embryo transfer （IVF-ET）. Methods A retrospective study was performed on women carrying monozygotic twins （MZTs） after conventional IVF-ET treatment at the Third Affiliated Hospital of Guangzhou Medical College in China from January 2003 to May 2009. The incidence and the miscarriage rate for MZTs following IVF-ET were examined iin relation to maternal age, duration of infertility, type and dose of hormone treatment, conventional IVF-ET cycles versus intracytoplasmic sperm injection （ICSI） cycles, the use of fresh or frozen-thawed embryos, and day （post-fertilization） of embryo transfer. Results Sixteen MZT pregnancies occurred in 2 161 patients （incidence of 0.74%）, of which 5 miscarried （31.25%）. No significant difference was found between MZT and non-MZT groups in terms of maternal age, duration of infertilit）, duration of gonadotropin （Gn） administration, dosage of Gn, number of oocytes retrieved, number of oocytes fertilized, or number of embryos transferred （P〉O.05）. The incidence of MZT was not statistically different between conventional IVF-ET cycles and ICSI cycles, between fresh embryos transfer cycles and frozen-thawed embryo cycles, or between different transfer days （P〉0.05）. Conclusion The incidence of MZTs following IVF-ET treatment greatly exceeds that observed following spontaneous conception. Intracytoplasmic sperm injection, frozenthawed procedures, and embryo transfer on different days were not correlated with an increased incidence of MZT pregnancies.展开更多
基金China’s National Natural Science Foundation provided funding for this study(81900222)Guangzhou Science and Technology Program(SL2022A04J01269,202201020646)Guangzhou Health Science and Technology Program(20211A010026).
文摘Aims:Multiple genes and environmental factors are known to be involved in congenital heart disease(CHD),but epigenetic variation has received little attention.Monozygotic(MZ)twins with CHD provide a unique model for exploring this phenomenon.In order to investigate the potential role of Deoxyribonucleic Acid(DNA)methyla-tion in CHD pathogenesis,the present study examined DNA methylation variation in MZ twins discordant for CHD,especially ventricular septal defect(VSD).Methods and Results:Using genome-wide DNA methylation profiles,we identified 4004 differentially methylated regions(DMRs)in 18 MZ twin pairs discordant for CHD,and 2826 genes were identified.Gene Ontology(GO)and Kyoto Encyclopedia of Genes and Genomes(KEGG)analysis revealed a list of CHD-associated pathways.To further investigate the role of DNA methylation in VSD,data from 7 pairs of MZ twins with VSD were analyzed.We identified 1614 DMRs corresponding to 1443 genes associated with arrhythmogenic right ventricular cardiomyopathy,cyclic guanosine monopho-sphate-protein kinase G(cGMP-PKG)signaling pathway by KEGG analysis,and cell-cell adhesion,calcium ion transmembrane transport by GO analysis.A proportion of DMR-associated genes were involved in calcium signaling pathways.The methylation changes of calcium signaling genes might be related to VSD pathogenesis.Conclusion:CHD is associated with differential DNA methylation in MZ twins.CHD may be etiologically linked to DNA methylation,and methylation of calcium signaling genes may be involved in the development of VSD.
文摘We are reporting a case of monozygotic twinning after donor egg intracytoplasmic sperm injection (ICSI). A 34-year-old lady presented to our centre with primary infertility due to severe endometriosis and low egg reserve. ICSI with donor eggs was planned. A 24 years old voluntary oocyte donor was investigated and stimulated under antagonist protocol. Total 21 eggs and all in metaphaseⅡwere retrieved. These eggs were injected with the patient's husband sperms by ICSI. Patient's endometrial lining was prepared under hormonal replacement therapy protocol. Two expanded blastocysts were transferred on day 5 of progesterone. Beta human chorionic gonadotropin was positive after 10 days. The first antenatal scan at 6 weeks could pick up only two sacs indicating twin conception. Repeat scan at 12 weeks revealed tri-amniotic triplet conception with two foetuses sharing the same placenta (triamniotic pregnancy with monochorionic twins). The patient was counselled about risks associated with triplet conception and was advised of embryo reduction. Two mono chorionic twins were reduced under ultrasonography guidance. Single pregnancy continued till 21 weeks after which the patient miscarried spontaneously. It is difficult to identify the subset of patients at risk for monozygotic twinning;hence, all patients should be counselled about possibility of monozygotic twinning while deciding the number of embryos to be transferred.
基金supported by the Strategic Priority Research Program (B) of the Chinese Academy of Sciences (XDB02020003 and XDB02030002)the Bureau of Frontier Sciences and Education,Chinese Academy of Sciences (QYZDJ-SSW-SMC005)+3 种基金the National Natural Science Foundation of China (Nos. 81088001,81271484,81471361 and 81371480)the Beijing Training Project for the Leading Talents in S & T (Z151100000315020)the National Key Basic Research and Development Program (973) (2012CB517904)the CAS/SAFEA International Partnership Programme for Creative Research Teams (Y2CX131003)
文摘Schizophrenia is a common disorder with a high heritability, but its genetic architecture is still elusive.We implemented whole-genome sequencing(WGS) analysis of 8 families with monozygotic(MZ) twin pairs discordant for schizophrenia to assess potential association of de novo mutations(DNMs) or inherited variants with susceptibility to schizophrenia. Eight non-synonymous DNMs(including one splicing site) were identified and shared by twins, which were either located in previously reported schizophrenia risk genes(p.V24689 I mutation in TTN, p.S2506 T mutation in GCN1L1, IVS3+1G > T in DOCK1) or had a benign to damaging effect according to in silico prediction analysis. By searching the inherited rare damaging or loss-of-function(LOF) variants and common susceptible alleles from three classes of schizophrenia candidate genes, we were able to distill genetic alterations in several schizophrenia risk genes, including GAD1, PLXNA2, RELN and FEZ1. Four inherited copy number variations(CNVs; including a large deletion at 16p13.11) implicated for schizophrenia were identified in four families, respectively. Most of families carried both missense DNMs and inherited risk variants, which might suggest that DNMs, inherited rare damaging variants and common risk alleles together conferred to schizophrenia susceptibility. Our results support that schizophrenia is caused by a combination of multiple genetic factors, with each DNM/variant showing a relatively small effect size.
基金a grant from the National Natural Science Foundation of China
文摘Background： Schizophrenia （SCZ） is a severe, debilitating, and complex psychiatric disorder with multiple causative factors. An increasing number of studies have determined that rare variations play an important role in its etiology. A somatic mutation is a rare form of genetic variation that occurs at an early stage of embryonic development and is thought to contribute substantially to the development of SCZ. The aim of the study was to explore the novel pathogenic somatic single nucleotide variations （SNVs） and somatic insertions and deletions （indels） of SCZ. Methods： One Chinese family with a monozygotic （MZ） twin pair discordant for SCZ was included. Whole exome sequencing was performed in the co-twin and their parents. Rigorous filtering processes were conducted to prioritize pathogenic somatic variations, and all identified SNVs and indels were further confirmed by Sanger sequencing. Results： One somatic SNV and two somatic indels were identified after rigorous selection processes. However, none was validated by Sanger sequencing. Conclusions： This study is not alone in the failure to identify pathogenic somatic variations in MZ twins, suggesting that exonic somatic variations are extremely rare. Further efforts are warranted to explore the potential genetic mechanism of SCZ.
基金funded by the National Key R&D Program of China(2018YFC1002900)National Natural Science Foundation of China(82071656)+1 种基金Shanghai Shenkang Hospital Development Center(SHDC2020CR6028-005)the research program of Shanghai First Maternity and Infant hospital(2019B05)。
文摘Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder characterized by the development of hamartomas in the brain, heart, skin, kidney, lung, retina, and so on. One fetus from family 1 had a cardiac rhabdomyoma from 21 weeks and 6 days of gestational age, and developed multiple rhabdomyomas and tubers in the brain at 23 weeks and 5 days. The counter monozygotic twin fetus remained negative throughout the pregnancy according to imaging examination. A nonsense mutation inTSC2 (c.4762C>T, p.Gln1588*) was identified in both twins, but not in the mother. Family 2 was one pair of twin fetuses caused by a microdeletion of exon 30 withinTSC2 inherited from their apparently asymptomatic mother with mosaic status. The larger fetus was identified as having the first cardiac rhabdomyoma from 17 weeks and 4 days of gestational age. The smaller fetus developed multiple rhabdomyomas until 25 weeks and 6 days of gestational age. Both families terminated the pregnancy. Here, we provide intrauterine examples of clinical variability among monozygotic twins suffering from TSC.
基金supported by the National Natural Science Foundation of China(Grant Nos.31471115,31401160,81300393,and 81300394)the Strategic Priority Research Program of the Chinese Academy of Sciences,Stem Cell and Regenerative Medicine Research,China(Grant No.XDA01040405)+4 种基金the National‘‘Twelfth Five-Year”Plan for Science&Technology Support,China(Grant No.2013BAI01B09)the National Key Scientific Instrument and Equipment Development Projects of China(Grant No.2011YQ03013404)the National High-tech R&D Program of China(Grant Nos.2015AA020101 and 2015AA020108)the State Key Laboratory of Experimental Hematology Pilot Project(Grant No.ZK13-05)the Nature Science Fund of Tianjin Municipal Science and Technology Commission,China(Grant No.12ZCDZSY18100)
文摘Primary myelofibrosis （PMF） is a chronic myeloproliferative disorder in human bone marrow. Over 50% of patients with myelofibrosis have mutations in JAK2, MPL, or CALR. However, these mutations are rarely detected in children, suggesting a difference in the pathogenesis of childhood PMF. In this study, we investigated the response to drug treatment of a monozygotic twin pair with typical childhood PMF. The twin exhibited different clinical outcomes despite following
文摘Objectives To study the incidence and potential causes of monozygotic twins after in vitro fertilization and embryo transfer （IVF-ET）. Methods A retrospective study was performed on women carrying monozygotic twins （MZTs） after conventional IVF-ET treatment at the Third Affiliated Hospital of Guangzhou Medical College in China from January 2003 to May 2009. The incidence and the miscarriage rate for MZTs following IVF-ET were examined iin relation to maternal age, duration of infertility, type and dose of hormone treatment, conventional IVF-ET cycles versus intracytoplasmic sperm injection （ICSI） cycles, the use of fresh or frozen-thawed embryos, and day （post-fertilization） of embryo transfer. Results Sixteen MZT pregnancies occurred in 2 161 patients （incidence of 0.74%）, of which 5 miscarried （31.25%）. No significant difference was found between MZT and non-MZT groups in terms of maternal age, duration of infertilit）, duration of gonadotropin （Gn） administration, dosage of Gn, number of oocytes retrieved, number of oocytes fertilized, or number of embryos transferred （P〉O.05）. The incidence of MZT was not statistically different between conventional IVF-ET cycles and ICSI cycles, between fresh embryos transfer cycles and frozen-thawed embryo cycles, or between different transfer days （P〉0.05）. Conclusion The incidence of MZTs following IVF-ET treatment greatly exceeds that observed following spontaneous conception. Intracytoplasmic sperm injection, frozenthawed procedures, and embryo transfer on different days were not correlated with an increased incidence of MZT pregnancies.
