BACKGROUND Dyschromatosis universalis hereditaria(DUH)is a rare type of autosomal dominant inheritance disease.It has varying gene mutation sites among different ethnicities.SASH1 and ABCB6 have been identified as the...BACKGROUND Dyschromatosis universalis hereditaria(DUH)is a rare type of autosomal dominant inheritance disease.It has varying gene mutation sites among different ethnicities.SASH1 and ABCB6 have been identified as the causative genes of this disorder.CASE SUMMARY A 30-year-old woman presented with irregular black pigmentation spots to our department.Upon examination,the pigmentations were found to be especially dense on the extremities and the face.She had no family history of inbreeding,nor any previous chemical exposure.Genetic testing confirmed that the disease occu-rred because the patient has a SASH1 gene mutation.Following the use of assisted reproductive technology and preimplantation genetic testing for monogenic disorders,the patient give birth to a health baby.CONCLUSION Using assisted reproductive technology/preimplantation genetic testing for monogenic disorders is an option for DUH patients to reduce the risk of trans-mitting the pathogenic variant to their offspring.展开更多
The paper looks at how to regulate access to genetic testing,other than through a medical practitioner as part of health services provision.It examines the steps by which genetic testing services may be obtained from ...The paper looks at how to regulate access to genetic testing,other than through a medical practitioner as part of health services provision.It examines the steps by which genetic testing services may be obtained from laboratories and the implications of these processes for individual access to testing services.It also discusses the quality assurance and accreditation standards which regulate genetic testing laboratories.Further,this paper looks into issues concerning the availability of home use testing or over-the-counter.Furthermore,we consider whether there should be additional legal protection against the taking and testing of genetic samples without the knowledge and consent of the individual concerned through the use of criminal sanctions.展开更多
Objective: Hereditary breast and ovarian cancer syndrome (HBOC) increases the risk of developing breast, ovarian, prostate, and pancreatic cancers. With the insurance coverage for BRCA genetic testing, the number of i...Objective: Hereditary breast and ovarian cancer syndrome (HBOC) increases the risk of developing breast, ovarian, prostate, and pancreatic cancers. With the insurance coverage for BRCA genetic testing, the number of individuals diagnosed with HBOC has increased. To use these test results effectively, cascade genetic testing (CGT) is recommended for at-risk relatives;however, it is not yet widely available. The purpose of this study was to investigate the willingness of the general population to share genetic test results and undergo CGT, as well as to analyze the factors influencing these decisions. Based on these findings, the study aimed to identify the types of support needed to support the sharing of genetic test results and promote the use of CGT. Methods: An online survey was conducted with 500 participants (50 men and women from each of the five generations, ranging from 20 to 69 years). Results: Among the HBOC blood relatives, 51.2% wanted to share the genetic results and 71.9% expressed a willingness to undergo CGT. “Matters to be shared with relatives” and “Helpful for my cancer prevention” were identified as key factors promoting the willingness to share the BRCA genetic test results and undergo CGT. The motivation for “Helpful for my cancer prevention” had a particularly strong influence on the decision to undergo CGT. Conclusion: In the general population, there is an emerging understanding that the genetic information impacts not only the individuals but also their entire families and can be valuable for cancer prevention. To promote the sharing of BRCA genetic test results and CGT uptake, the healthcare providers should offer support tailored to each family’s circumstances and establish cancer prevention measures recommended for HBOC.展开更多
Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians.Given the lack of ac...Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians.Given the lack of access to geneticists,medical oncologists and other treating physicians have begun ordering and interpreting genetic tests for individuals with cancer through the process of"mainstreaming".While this process has allowed for quicker access to genetic tests,the process of"mainstreaming"has also brought several challenges including the dissemination of variants of unknown significance results,ordering of appropriate tests,and accurate interpretation of genetic results with appropriate followup testing and interventions.In this editorial,we seek to explore the process of informed consent of individuals before obtaining genetic testing and offer potential solutions to optimize the informed consent process including categorization of results as well as a layered consent model.展开更多
Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous ...Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.展开更多
Invasive genetic screening of pre-implantation embryos via biopsied trophectoderm(TE)cells has been in use for more than 20 years,while its benefits in selecting euploid embryos remain controversial.Recent advances in...Invasive genetic screening of pre-implantation embryos via biopsied trophectoderm(TE)cells has been in use for more than 20 years,while its benefits in selecting euploid embryos remain controversial.Recent advances in the ability to process embryonic cell-free DNA(cfDNA)from blastocoel fluid(BF)and spent culture media(SCM)of blastocysts in a manner similar to that of a biopsied TE sample provide a potential alternative holding great promise for obtaining cytogenetic information of the embryos without intrusive biopsy of traditional biopsy-based pre-implantation genetic testing(PGT).Several studies have reported even higher diagnostic accuracy in non-invasive PGT(ni-PGT)than conventional PGT.However,there are still several technical challenges to be overcome before ni-PGT can be accepted as a reliable genomic information source of embryo.In this review,we have summarized the emergence and current state of ni-PGT,and discussed our own perspectives on their limitations and future prospect.There is still a long way to go before truly wide clinical application of ni-PGT.展开更多
Objective:To investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer patients with indications for breast cancer susceptibility genes 1/2(BRCA1/2)genetic testing in Chin...Objective:To investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer patients with indications for breast cancer susceptibility genes 1/2(BRCA1/2)genetic testing in China.Methods:Based on the indication criteria for BRCA genetic testing specified in the National Comprehensive Cancer Network(NCCN)clinical practice guidelines in oncology,genetic/familial high-risk assessment:Breast and ovarian(Version 2.2019),a retrospective analysis was performed on patients with early-stage invasive breast cancer treated at Breast Disease Center,Peking University First Hospital between January 2008 and December 2016.Clinicopathological characteristics of all patients were analyzed,and prognoses were calculated using the KaplanMeier method and a Cox proportionate hazards model.Results:A total of 906 early-stage breast cancer patients who had indications for BRCA genetic testing and had complete clinicopathological data and follow-up information were included in the study group,accounting for34.7%of all breast cancer patients treated in Breast Disease Center,Peking University First Hospital during the study period.Compared with breast cancer patients without indications for BRCA genetic testing,the overall survival(OS)and disease-free survival(DFS)of patients with indications were not significantly different.In the study group,patients with premenopausal status,high T stage,lymph node positive,estrogen receptor(ER)negative,Ki-67>20%and presence of a vascular tumor thrombus had worse prognosis.There were more family histories of gastrointestinal cancer in patients with related indications than in patients without such indications.Conclusions:Single-center data showed that more than 30%of patients with early-stage breast cancer had indications for BRCA genetic testing.There was no prognostic difference in patients with or without indications for BRCA genetic testing.Premenopausal status,high T stage,lymph node positive,ER negative,Ki-67>20%,and presence of a vascular tumor thrombus were associated with poor prognosis.展开更多
BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH childr...BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.展开更多
Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies.As novel mutations have been identified,understanding when to ...Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies.As novel mutations have been identified,understanding when to consider genetic testing has emerged as an important consideration in the management of these cases.Specific genetic testing has a paramount importance in the risk stratification of family members,in the prognosis of probands at higher risk of a serious phenotype expression,and finally in the identification of new mutations,all of which are discussed in this review.The indications for each type of cardiomyopathy are described,along with the limitations of genetic testing.Finally,the importance of public sharing of variants in large data sets is emphasized.The ultimate aim of this review is to present key messages about the genetic testing process in order to minimize potential harms and provide suggestions to specialized clinicians who act as a part of a multidisciplinary team in order to offer the best care to families with inherited cardiomyopathies.展开更多
BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple gen...BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.展开更多
BACKGROUND An inconclusive result from BRCA1/2 genetic testing indicates that a genetic variant of uncertain significance is detected.This case constitutes the majority of genetic test results,but studies specifically...BACKGROUND An inconclusive result from BRCA1/2 genetic testing indicates that a genetic variant of uncertain significance is detected.This case constitutes the majority of genetic test results,but studies specifically addressing the psychological adjustment of people with inconclusive results are scarce.AIM To examine psychological outcomes of receiving an uninformative BRCA1/2 test result.METHODS PubMed,PsychInfo,and Cochrane Central Register of Controlled Trials were screened for studies focusing on distress,anxiety,and depression levels in individuals with inconclusive genetic test results.This review is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method.RESULTS Studies on psychological outcomes of inconclusive BRCA1/2 focused on general and specific distress,anxiety,and depression.Overall,they produced mixed results.These inconsistent findings are probably due to the uncertainty caused by this type of result,that may also influence the decisions of individuals about surveillance and prophylactic options,reducing their compliance.In addition,this review highlights specific risk and protective factors that affect psychological adjustment in individuals with an inconclusive genetic testing result.CONCLUSION Individuals with inconclusive genetic test results need specific educational programs and support to better understand the meaning of their results in order to be able to make decisions about surveillance and prophylactic options.展开更多
Recurrent spontaneous abortion (RSA) is a complex and heterogeneous disorder with multiple etiologies. Genetic factors are thought to play an important role in the etiology of RSA. With recent advances in genetic test...Recurrent spontaneous abortion (RSA) is a complex and heterogeneous disorder with multiple etiologies. Genetic factors are thought to play an important role in the etiology of RSA. With recent advances in genetic testing technologies, there has been an increasing interest in using these tools to diagnose the etiology of RSA. This review discusses the different types of genetic testing methods, such as karyotyping, chromosomal microarray analysis, next-generation sequencing, and their applications in the diagnosis of the etiology RSA. The use of genetic testing in the diagnosis of RSA has the potential to improve the accuracy of diagnosis and the understanding of the underlying mechanisms of the disorder, which could lead to better management and treatment of affected individuals.展开更多
Preimplantation genetic testing(PGT),which was developed as an alternative to prenatal genetic testing,allows couples to avoid pregnancies with abnormal chromosomes and the subsequent termination of the affected fetus...Preimplantation genetic testing(PGT),which was developed as an alternative to prenatal genetic testing,allows couples to avoid pregnancies with abnormal chromosomes and the subsequent termination of the affected fetus.Originally used for early onset monogenic conditions,PGT is now used to prevent various types of inherited cancer conditions based on the development of PGT technology,assisted reproductive techniques(ARTs),and in vitro fertilization(IVF).This review provides insights into the potential benefits and challenges associated with the application of PGT for hereditary cancer and provides an overview of the existing literature on this test,with a particular focus on the current challenges related to laws,ethics,counseling,and technology.Additionally,this review predicts the future potential applications of this method.Although PGT may be utilized to predict and prevent hereditary cancer,each case should be comprehensively evaluated.The motives of couples must be assessed to prevent the misuse of this technique for eugenic purposes,and non-pathogenic phenotypes must be carefully evaluated.Pathological cases that require this technology should also be carefully considered based on legal and ethical reasoning.PGT may be the preferred treatment for hereditary cancer cases;however,such cases require careful case-by-case evaluations.Therefore,this study concludes that multidisciplinary counseling and support for patients and their families are essential to ensure that PGT is a viable option that meets all legal and ethical concerns.展开更多
Congenital heart disease(CHD)encompasses a range of structural malformations affecting the heart and major blood vessels present at birth.The genetic under-pinnings of CHD have long been recognized as pivotal,facilita...Congenital heart disease(CHD)encompasses a range of structural malformations affecting the heart and major blood vessels present at birth.The genetic under-pinnings of CHD have long been recognized as pivotal,facilitated by a deeper mo-lecular understanding of cardiogenesis.Various genetic variants,including single nucleotide variations,structural variations,and chromosomal abnormalities,have been identified in association with both syndromic and non-syndromic CHD.As ge-netic technologies evolve and improve,the application of genetic testing in CHD patients promises to yield valuable insights for both clinical practice and basic sci-ence.With the advancement of cohort studies,genomic data on these variations can be robustly collected and classified according to their pathogenicity,thereby en-hancing our understanding of CHD genetics.Numerous tools have been developed to interpret variants identified in both coding and non-coding regions through genetic testing,providing substantial reference points for clinical decision-making in CHD management.The integration of genetic testing stands to benefit CHD management across various fronts,including diagnosis,prognosis prediction,and recurrence risk estimation.A thorough understanding of the genetic investigations and clinical practices related to CHD genetics is essential for the advanced application of genetic testing in CHD cases.By leveraging this knowledge,healthcare professionals can effectively incorporate genetic testing into the broader framework of CHD care,ul-timately improving patient outcomes and advancing our understanding of these complex conditions.展开更多
Fluoropyrimidines(FP),including 5-fluorouracil and its prodrug capecitabine,are commonly employed in treating various solid tumors.Nonetheless,their use is frequently constrained by severe toxicities in 20%-30%of pati...Fluoropyrimidines(FP),including 5-fluorouracil and its prodrug capecitabine,are commonly employed in treating various solid tumors.Nonetheless,their use is frequently constrained by severe toxicities in 20%-30%of patients.Pharmacogenetic testing for dihydropyrimidine dehydrogenase(DPYD)deficiency,based on DPYD polymorphisms,has notably decreased severe adverse events,improving the safety of FP therapy.A recent D'Amato et al study evaluated the prevalence of DPYD polymorphisms and their effect on FP tolerability among Italian patients with gastrointestinal cancers.Although this study provided important insights into the significance of DPYD testing,its retrospective nature,inconsistency in testing DPYD variants,and lack of consideration for socioeconomic and confounding factors showed considerable limitations.Expanding the screening to include DPYD variants,addressing confounding biases through robust statistical analyses,and implementing prospective studies are critical next steps to strengthen the clinical evidence.Furthermore,the absence of a comprehensive cost-effectiveness analysis highlights the need for further financial assessments to advocate for broader implementation.We emphasized integrating DPYD-guided dosing,pre-treatment genetic counseling,and standardized testing procedures into clinical practice to improve patient outcomes and minimize treatment-related toxicities.展开更多
Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),is an inherited condition associated with a higher risk of colorectal cancer(CRC)and other cancers.It is caused by germline mutations ...Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),is an inherited condition associated with a higher risk of colorectal cancer(CRC)and other cancers.It is caused by germline mutations in DNA mismatch repair(MMR)genes,including MLH1,MSH2,MSH6 and PMS2.These mutations lead to microsatellite instability(MSI)and defective DNA repair mechanisms,resulting in increased cancer risk.Early detection of LS is crucial for effective management and cancer prevention.Endoscopic surveillance,particularly regular colonoscopy,is recommended for individuals with LS to detect CRC at early stages.Additionally,universal screening of CRC for MMR deficiency can help identify at-risk individuals.Genetic counseling plays a valuable role in LS by guiding patients and their families in understanding the genetic basis,making informed decisions regarding surveillance and prevention,and offering reproductive options to reduce the transmission of pathogenic variants of the offspring.The aim of this review is to outline current strategies for the diagnosis,surveillance,and management of LS,with a focus on the role of genetic counseling,endoscopic screening,and emerging therapeutic approaches to mitigate cancer risk in affected individuals.展开更多
Objective:To evaluate whether preimplantation genetic testing for aneuploidy(PGT-A)with comprehensive chromosome screening increases live birth rate(LBR)in normal karyotype couples with recurrent pregnancy loss(RPL).M...Objective:To evaluate whether preimplantation genetic testing for aneuploidy(PGT-A)with comprehensive chromosome screening increases live birth rate(LBR)in normal karyotype couples with recurrent pregnancy loss(RPL).Methods:A retrospective cohort follow-up study of 506 couples with RPL was conducted between April 2014 and March 2017.Couples were allocated to two groups according to their decision to choose PGT-A or not.The primary outcome was LBR per start/transfer cycle;secondary outcomes were ongoing pregnancy rate and miscarriage rate.Statistical analyses were conducted using univariate and multivariate logistic regression models adjusted for maternal age.Results:LBR per start(26.6%vs.15.4%,relative risk[RR]:2.66,95%confidence interval[CI][1.69-4.20],P<0.0001;adjusted RR[aRR]:2.40,95%CI[1.49-3.86],P=0.0004)and per transfer(44.9%vs.25.1%,RR:3.00,95%CI[1.96-4.60],P<0.0001;aRR:2.64,95%CI[1.68-4.14],P<0.0001)was significantly higher in the PGT-A group than in the non-PGT-A group.The miscarriage rate was significantly lower in the PGT-A group compared to the non-PGT-A group(15.7%vs.34.6%,RR:0.27,95%CI[0.13-0.57],P=0.00005;aRR:0.26,95%CI[0.12-0.57],P=0.0007).Conclusions:LBR per start cycle following PGT-A is significantly higher,and risk of miscarriage is significantly lower among infertile couples with RPL,irrespective of maternal age.PGT-A should be recommended to infertile couples with RPL.展开更多
Objective:To evaluate the effect of preimplantation genetic testing for aneuploidy(PGT-A)in infertile patients with recurrent pregnancy loss(RPL).Methods:A prospective randomized clinical trial was performed in a univ...Objective:To evaluate the effect of preimplantation genetic testing for aneuploidy(PGT-A)in infertile patients with recurrent pregnancy loss(RPL).Methods:A prospective randomized clinical trial was performed in a university-affiliated fertility center in Shanghai,China.Patients in the PGT-A group underwent blastocyst biopsy followed by single-nucleotide polymorphism microarray-based PGT-A and single euploid blastocyst transfer,whereas patients in the control group underwent routine in vitro fertilization/ICSI procedures and frozen embryo transfer of 1-2 embryos selected according to morphological standards.Results:Two hundred and seven infertile patients with RPL were included in this study and randomly assigned to either the control or the PGT-A group.Baseline variables and cycle characteristics were comparable between the two groups.The results showed that PGT-A significantly improved the ongoing pregnancy rate(55.34%vs.29.81%)as well as the live birth rate(48.54%vs.27.88%)and significantly reduced the miscarriage rate(0.00%vs.14.42%)on a per-patient analysis.A significant increase in cumulative ongoing pregnancy rates over time was observed in the PGT-A group.Subgroup analysis showed that the significant benefit diminished for patients who attempted≥2 PGT-A cycles.Conclusions:PGT-A significantly improved the ongoing pregnancy and live birth rate,while reduced miscarriage rate in infertile RPL patients.However,the significance diminished in patients attempting≥2 cycles;thus,further studies are warranted to explore the most cost-effective number of attempts in these patients to avoid overuse.展开更多
The first practice of pre-implantation genetic testing(PGT)was reported more than 30 years ago.PGT,originally named preimplantation genetic screening(PGS)and pre-implantation genetic diagnosis(PGD),is now categorized ...The first practice of pre-implantation genetic testing(PGT)was reported more than 30 years ago.PGT,originally named preimplantation genetic screening(PGS)and pre-implantation genetic diagnosis(PGD),is now categorized as PGT for aneuploidies(PGT-A),PGT for monogenic/single-gene defects(PGT-M),and PGT for chromosomal structural rearrangements(PGT-SR).Patients with fertility issues caused by advanced maternal age,carrier status of chromosomal abnormalities,or harboring pathogenic variant(s)are recommended to undergo PGT to increase the possibility of successful live birth and avoid potentially affected newborns.High-throughput techniques,such as DNA microarrays and next-generation sequencing(NGS),have enabled comprehensive screening of all 24 chromosomes,instead of few loci at a time.Furthermore,as a comprehensive PGT,PGT-Plus was enabled by the rapid development of a genome-wide single-cell haplotyping technique to detect embryo aneuploidy,single-gene disorders,and chromosomal aberrations simultaneously using a single universal protocol.In addition,non-invasive approaches enable a more intact embryo during the biopsy procedure,which may avoid potential mosaicism issues at a certain scale by testing spent culture media(SCM).As a novel PGT application,PGT-P detects genome-wide variations in polygenic diseases,which account for a large proportion of premature human deaths and affect a markedly larger population than monogenic diseases,using polygenic risk score calculation to decrease the potential of affecting complex conditions.Owing to the emergence of new technologies recruited to PGTs,more couples with infertility issues have a promising chance of conceiving a healthy baby,ultimately facilitating the human species to live more prosper.展开更多
Preimplantation genetic testing(PGT)is an early form of prenatal genetic diagnosis,which can identify the abnormal embryos cultured in vitro,allow only transfer of genetically normal embryos,and improve the pregnancy ...Preimplantation genetic testing(PGT)is an early form of prenatal genetic diagnosis,which can identify the abnormal embryos cultured in vitro,allow only transfer of genetically normal embryos,and improve the pregnancy rate.In recent years,the rapid development of microarrays and next-generation sequencing(NGS)technologies has remarkably accelerated the clinical application of PGT.In particular,a variety of detection methods have emerged and achieved significant progress in PGT for structural rearrangements(PGT-SR).The detection-related abilities of these methods range from the detection of limited chromosome aneuploidy to comprehensive chromosome screening of the whole genome to differentiation of embryos with normal or balanced translocation/inversion karyotypes.In this study,we reviewed PGT-SR-related detection techniques to provide a better reference for clinical application and research.We have also discussed the potential development of novel techniques in the future.展开更多
文摘BACKGROUND Dyschromatosis universalis hereditaria(DUH)is a rare type of autosomal dominant inheritance disease.It has varying gene mutation sites among different ethnicities.SASH1 and ABCB6 have been identified as the causative genes of this disorder.CASE SUMMARY A 30-year-old woman presented with irregular black pigmentation spots to our department.Upon examination,the pigmentations were found to be especially dense on the extremities and the face.She had no family history of inbreeding,nor any previous chemical exposure.Genetic testing confirmed that the disease occu-rred because the patient has a SASH1 gene mutation.Following the use of assisted reproductive technology and preimplantation genetic testing for monogenic disorders,the patient give birth to a health baby.CONCLUSION Using assisted reproductive technology/preimplantation genetic testing for monogenic disorders is an option for DUH patients to reduce the risk of trans-mitting the pathogenic variant to their offspring.
文摘The paper looks at how to regulate access to genetic testing,other than through a medical practitioner as part of health services provision.It examines the steps by which genetic testing services may be obtained from laboratories and the implications of these processes for individual access to testing services.It also discusses the quality assurance and accreditation standards which regulate genetic testing laboratories.Further,this paper looks into issues concerning the availability of home use testing or over-the-counter.Furthermore,we consider whether there should be additional legal protection against the taking and testing of genetic samples without the knowledge and consent of the individual concerned through the use of criminal sanctions.
文摘Objective: Hereditary breast and ovarian cancer syndrome (HBOC) increases the risk of developing breast, ovarian, prostate, and pancreatic cancers. With the insurance coverage for BRCA genetic testing, the number of individuals diagnosed with HBOC has increased. To use these test results effectively, cascade genetic testing (CGT) is recommended for at-risk relatives;however, it is not yet widely available. The purpose of this study was to investigate the willingness of the general population to share genetic test results and undergo CGT, as well as to analyze the factors influencing these decisions. Based on these findings, the study aimed to identify the types of support needed to support the sharing of genetic test results and promote the use of CGT. Methods: An online survey was conducted with 500 participants (50 men and women from each of the five generations, ranging from 20 to 69 years). Results: Among the HBOC blood relatives, 51.2% wanted to share the genetic results and 71.9% expressed a willingness to undergo CGT. “Matters to be shared with relatives” and “Helpful for my cancer prevention” were identified as key factors promoting the willingness to share the BRCA genetic test results and undergo CGT. The motivation for “Helpful for my cancer prevention” had a particularly strong influence on the decision to undergo CGT. Conclusion: In the general population, there is an emerging understanding that the genetic information impacts not only the individuals but also their entire families and can be valuable for cancer prevention. To promote the sharing of BRCA genetic test results and CGT uptake, the healthcare providers should offer support tailored to each family’s circumstances and establish cancer prevention measures recommended for HBOC.
文摘Recent advancements in next generation sequencing have allowed for genetic information become more readily available in the clinical setting for those affected by cancer and by treating clinicians.Given the lack of access to geneticists,medical oncologists and other treating physicians have begun ordering and interpreting genetic tests for individuals with cancer through the process of"mainstreaming".While this process has allowed for quicker access to genetic tests,the process of"mainstreaming"has also brought several challenges including the dissemination of variants of unknown significance results,ordering of appropriate tests,and accurate interpretation of genetic results with appropriate followup testing and interventions.In this editorial,we seek to explore the process of informed consent of individuals before obtaining genetic testing and offer potential solutions to optimize the informed consent process including categorization of results as well as a layered consent model.
文摘Next generation sequencing is currently a cornerstone of genetic testing in routine diagnostics,allowing for the detection of sequence variants with so far unprecedented large scale,mainly in genetically heterogenous diseases,such as neurological disorders.It is a fast-moving field,where new wet enrichment protocols and bioinformatics tools are constantly being developed to overcome initial limitations.Despite the as yet undiscussed advantages,however,there are still some challenges in data analysis and the interpretation of variants.In this review,we address the current state of next generation sequencing diagnostic testing for inherited human disorders,particularly giving an overview of the available high-throughput sequencing approaches;including targeted,whole-exome and whole-genome sequencing;and discussing the main critical aspects of the bioinformatic process,from raw data analysis to molecular diagnosis.
基金We thank professors Cynthia Casson Morton and Yiping Shen from Harvard Medical School and professor Sharon YC Ruan from Hong Kong Polytechnic University for revising the manuscript.This work was supported by the National Key Research and Development Program of China(2018YFC1005003)the National Natural Science Foundation of China(81974224,81771535)+2 种基金the Natural Science Foundation of Zhejiang Province(LZ18H040001,LQ19H040007)Zhejiang Provincial Key Medical Technology Program(WKJ-ZJ-1826)Zhejiang University Education Foundation Global Partnership Fund.The authors declared no conflict of interest.
文摘Invasive genetic screening of pre-implantation embryos via biopsied trophectoderm(TE)cells has been in use for more than 20 years,while its benefits in selecting euploid embryos remain controversial.Recent advances in the ability to process embryonic cell-free DNA(cfDNA)from blastocoel fluid(BF)and spent culture media(SCM)of blastocysts in a manner similar to that of a biopsied TE sample provide a potential alternative holding great promise for obtaining cytogenetic information of the embryos without intrusive biopsy of traditional biopsy-based pre-implantation genetic testing(PGT).Several studies have reported even higher diagnostic accuracy in non-invasive PGT(ni-PGT)than conventional PGT.However,there are still several technical challenges to be overcome before ni-PGT can be accepted as a reliable genomic information source of embryo.In this review,we have summarized the emergence and current state of ni-PGT,and discussed our own perspectives on their limitations and future prospect.There is still a long way to go before truly wide clinical application of ni-PGT.
文摘Objective:To investigate the clinicopathological characteristics and prognostic factors of early-stage breast cancer patients with indications for breast cancer susceptibility genes 1/2(BRCA1/2)genetic testing in China.Methods:Based on the indication criteria for BRCA genetic testing specified in the National Comprehensive Cancer Network(NCCN)clinical practice guidelines in oncology,genetic/familial high-risk assessment:Breast and ovarian(Version 2.2019),a retrospective analysis was performed on patients with early-stage invasive breast cancer treated at Breast Disease Center,Peking University First Hospital between January 2008 and December 2016.Clinicopathological characteristics of all patients were analyzed,and prognoses were calculated using the KaplanMeier method and a Cox proportionate hazards model.Results:A total of 906 early-stage breast cancer patients who had indications for BRCA genetic testing and had complete clinicopathological data and follow-up information were included in the study group,accounting for34.7%of all breast cancer patients treated in Breast Disease Center,Peking University First Hospital during the study period.Compared with breast cancer patients without indications for BRCA genetic testing,the overall survival(OS)and disease-free survival(DFS)of patients with indications were not significantly different.In the study group,patients with premenopausal status,high T stage,lymph node positive,estrogen receptor(ER)negative,Ki-67>20%and presence of a vascular tumor thrombus had worse prognosis.There were more family histories of gastrointestinal cancer in patients with related indications than in patients without such indications.Conclusions:Single-center data showed that more than 30%of patients with early-stage breast cancer had indications for BRCA genetic testing.There was no prognostic difference in patients with or without indications for BRCA genetic testing.Premenopausal status,high T stage,lymph node positive,ER negative,Ki-67>20%,and presence of a vascular tumor thrombus were associated with poor prognosis.
基金Supported by the Fundamental Research Funds of Health Commission of Sichuan Province,No.17ZD035.
文摘BACKGROUND CYP21A2 gene mutations may all cause reduction or loss of 21-hydroxylase activity,leading to development of congenital adrenal hyperplasia(CAH)with different clinical phenotypes.For families with CAH children,genetic testing of the parents and genetic counseling are recommended to assess the risk of recurrence.CASE SUMMARY We report a case of CAH with a high suspicion before delivery.The risk of the child suffering from CAH during the pregnancy had been underestimated due to the deviation of genetic counseling and genetic testing results.Our report confirmed a CYP21A2 homozygous deletion in this case,CYP21A2 heterozygous deletion in the mother,and a rare 2+0 CYP21A2 deletion in the father.CONCLUSION It is important to analyze the distribution of CYP21A2 gene in the two alleles of parents of children with CAH.
文摘Recent advances in cardiovascular genetics have transformed genetic testing into a valuable part of management of families with inherited cardiomyopathies.As novel mutations have been identified,understanding when to consider genetic testing has emerged as an important consideration in the management of these cases.Specific genetic testing has a paramount importance in the risk stratification of family members,in the prognosis of probands at higher risk of a serious phenotype expression,and finally in the identification of new mutations,all of which are discussed in this review.The indications for each type of cardiomyopathy are described,along with the limitations of genetic testing.Finally,the importance of public sharing of variants in large data sets is emphasized.The ultimate aim of this review is to present key messages about the genetic testing process in order to minimize potential harms and provide suggestions to specialized clinicians who act as a part of a multidisciplinary team in order to offer the best care to families with inherited cardiomyopathies.
文摘BACKGROUND Identifying a potential single monogenetic disorder in healthy couples is costly due to the Assisted Reproduction facilities'current methodology for screening,which focuses on the detecting multiple genetic disorders at once.Here,we report the successful application of a low-cost and fast preimplantation genetic testing for monogenic/single gene defects(PGT-M)approach for detecting propionic acidemia(PA)in embryos obtained from a confirmed heterozygous propionyl-CoA carboxylase alpha subunit(PCCA)couple.CASE SUMMARY A fertile 32-years old Mexican couple with denied consanguinity sought antenatal genetic counseling.They were suspected obligate PA carriers due to a previous deceased PA male newborn with an unknown PCCA/propionyl-CoA carboxylase beta subunit(PCCB)genotype.Next-Generation Sequencing revealed a heterozygous genotype for a pathogenic PCCA variant(c.2041-1G>T,ClinVar:RCV-000802701.1;dbSNP:rs1367867218)in both parents.The couple requested in vitro fertilization(IVF)and PGT-M for PA.From IVF,12 oocytes were collected and fertilized,of which two resulted in high-quality embryos.Trophectoderm biopsies and Whole Genome Amplification by a fragmentation/amplification-based method were performed and revealed that the two embryos were euploid.Endpoint polymerase chain reaction and further Sanger sequencing of the exon-intron borders revealed a wild-type PCCA male embryo and a heterozygous c.2041-1G>T female embryo.Both embryos were transferred,resulting in a clinical pregnancy and the delivery of a healthy male newborn(38 wk,weight:4080 g,length:49 cm,APGAR 9/9).The absence of PA was confirmed by expanded newborn screening.CONCLUSION We show that using PGT-M with Whole Genome Amplification templates,coupled with IVF,can reduce the transmission of a pathogenic variant of the PCCA gene.
文摘BACKGROUND An inconclusive result from BRCA1/2 genetic testing indicates that a genetic variant of uncertain significance is detected.This case constitutes the majority of genetic test results,but studies specifically addressing the psychological adjustment of people with inconclusive results are scarce.AIM To examine psychological outcomes of receiving an uninformative BRCA1/2 test result.METHODS PubMed,PsychInfo,and Cochrane Central Register of Controlled Trials were screened for studies focusing on distress,anxiety,and depression levels in individuals with inconclusive genetic test results.This review is based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses method.RESULTS Studies on psychological outcomes of inconclusive BRCA1/2 focused on general and specific distress,anxiety,and depression.Overall,they produced mixed results.These inconsistent findings are probably due to the uncertainty caused by this type of result,that may also influence the decisions of individuals about surveillance and prophylactic options,reducing their compliance.In addition,this review highlights specific risk and protective factors that affect psychological adjustment in individuals with an inconclusive genetic testing result.CONCLUSION Individuals with inconclusive genetic test results need specific educational programs and support to better understand the meaning of their results in order to be able to make decisions about surveillance and prophylactic options.
文摘Recurrent spontaneous abortion (RSA) is a complex and heterogeneous disorder with multiple etiologies. Genetic factors are thought to play an important role in the etiology of RSA. With recent advances in genetic testing technologies, there has been an increasing interest in using these tools to diagnose the etiology of RSA. This review discusses the different types of genetic testing methods, such as karyotyping, chromosomal microarray analysis, next-generation sequencing, and their applications in the diagnosis of the etiology RSA. The use of genetic testing in the diagnosis of RSA has the potential to improve the accuracy of diagnosis and the understanding of the underlying mechanisms of the disorder, which could lead to better management and treatment of affected individuals.
文摘Preimplantation genetic testing(PGT),which was developed as an alternative to prenatal genetic testing,allows couples to avoid pregnancies with abnormal chromosomes and the subsequent termination of the affected fetus.Originally used for early onset monogenic conditions,PGT is now used to prevent various types of inherited cancer conditions based on the development of PGT technology,assisted reproductive techniques(ARTs),and in vitro fertilization(IVF).This review provides insights into the potential benefits and challenges associated with the application of PGT for hereditary cancer and provides an overview of the existing literature on this test,with a particular focus on the current challenges related to laws,ethics,counseling,and technology.Additionally,this review predicts the future potential applications of this method.Although PGT may be utilized to predict and prevent hereditary cancer,each case should be comprehensively evaluated.The motives of couples must be assessed to prevent the misuse of this technique for eugenic purposes,and non-pathogenic phenotypes must be carefully evaluated.Pathological cases that require this technology should also be carefully considered based on legal and ethical reasoning.PGT may be the preferred treatment for hereditary cancer cases;however,such cases require careful case-by-case evaluations.Therefore,this study concludes that multidisciplinary counseling and support for patients and their families are essential to ensure that PGT is a viable option that meets all legal and ethical concerns.
基金supported by the National Key Research and Development Program of China(2021YFC2701000 and 2021YFC2701004)the National Natural Science Foundation of China(82270312)the CAMS Innovation Fund for Medical Sciences(2019-I2M-5-002).
文摘Congenital heart disease(CHD)encompasses a range of structural malformations affecting the heart and major blood vessels present at birth.The genetic under-pinnings of CHD have long been recognized as pivotal,facilitated by a deeper mo-lecular understanding of cardiogenesis.Various genetic variants,including single nucleotide variations,structural variations,and chromosomal abnormalities,have been identified in association with both syndromic and non-syndromic CHD.As ge-netic technologies evolve and improve,the application of genetic testing in CHD patients promises to yield valuable insights for both clinical practice and basic sci-ence.With the advancement of cohort studies,genomic data on these variations can be robustly collected and classified according to their pathogenicity,thereby en-hancing our understanding of CHD genetics.Numerous tools have been developed to interpret variants identified in both coding and non-coding regions through genetic testing,providing substantial reference points for clinical decision-making in CHD management.The integration of genetic testing stands to benefit CHD management across various fronts,including diagnosis,prognosis prediction,and recurrence risk estimation.A thorough understanding of the genetic investigations and clinical practices related to CHD genetics is essential for the advanced application of genetic testing in CHD cases.By leveraging this knowledge,healthcare professionals can effectively incorporate genetic testing into the broader framework of CHD care,ul-timately improving patient outcomes and advancing our understanding of these complex conditions.
文摘Fluoropyrimidines(FP),including 5-fluorouracil and its prodrug capecitabine,are commonly employed in treating various solid tumors.Nonetheless,their use is frequently constrained by severe toxicities in 20%-30%of patients.Pharmacogenetic testing for dihydropyrimidine dehydrogenase(DPYD)deficiency,based on DPYD polymorphisms,has notably decreased severe adverse events,improving the safety of FP therapy.A recent D'Amato et al study evaluated the prevalence of DPYD polymorphisms and their effect on FP tolerability among Italian patients with gastrointestinal cancers.Although this study provided important insights into the significance of DPYD testing,its retrospective nature,inconsistency in testing DPYD variants,and lack of consideration for socioeconomic and confounding factors showed considerable limitations.Expanding the screening to include DPYD variants,addressing confounding biases through robust statistical analyses,and implementing prospective studies are critical next steps to strengthen the clinical evidence.Furthermore,the absence of a comprehensive cost-effectiveness analysis highlights the need for further financial assessments to advocate for broader implementation.We emphasized integrating DPYD-guided dosing,pre-treatment genetic counseling,and standardized testing procedures into clinical practice to improve patient outcomes and minimize treatment-related toxicities.
文摘Lynch syndrome(LS),also known as hereditary non-polyposis colorectal cancer(HNPCC),is an inherited condition associated with a higher risk of colorectal cancer(CRC)and other cancers.It is caused by germline mutations in DNA mismatch repair(MMR)genes,including MLH1,MSH2,MSH6 and PMS2.These mutations lead to microsatellite instability(MSI)and defective DNA repair mechanisms,resulting in increased cancer risk.Early detection of LS is crucial for effective management and cancer prevention.Endoscopic surveillance,particularly regular colonoscopy,is recommended for individuals with LS to detect CRC at early stages.Additionally,universal screening of CRC for MMR deficiency can help identify at-risk individuals.Genetic counseling plays a valuable role in LS by guiding patients and their families in understanding the genetic basis,making informed decisions regarding surveillance and prevention,and offering reproductive options to reduce the transmission of pathogenic variants of the offspring.The aim of this review is to outline current strategies for the diagnosis,surveillance,and management of LS,with a focus on the role of genetic counseling,endoscopic screening,and emerging therapeutic approaches to mitigate cancer risk in affected individuals.
基金This study was supported by Shanghai Municipal Commission of Health and Family Planning Project(No.201640365)Shanghai Shen Kang Hospital Development Center Municipal Hospital New Frontier Technology Joint Project(SHDC12017105).
文摘Objective:To evaluate whether preimplantation genetic testing for aneuploidy(PGT-A)with comprehensive chromosome screening increases live birth rate(LBR)in normal karyotype couples with recurrent pregnancy loss(RPL).Methods:A retrospective cohort follow-up study of 506 couples with RPL was conducted between April 2014 and March 2017.Couples were allocated to two groups according to their decision to choose PGT-A or not.The primary outcome was LBR per start/transfer cycle;secondary outcomes were ongoing pregnancy rate and miscarriage rate.Statistical analyses were conducted using univariate and multivariate logistic regression models adjusted for maternal age.Results:LBR per start(26.6%vs.15.4%,relative risk[RR]:2.66,95%confidence interval[CI][1.69-4.20],P<0.0001;adjusted RR[aRR]:2.40,95%CI[1.49-3.86],P=0.0004)and per transfer(44.9%vs.25.1%,RR:3.00,95%CI[1.96-4.60],P<0.0001;aRR:2.64,95%CI[1.68-4.14],P<0.0001)was significantly higher in the PGT-A group than in the non-PGT-A group.The miscarriage rate was significantly lower in the PGT-A group compared to the non-PGT-A group(15.7%vs.34.6%,RR:0.27,95%CI[0.13-0.57],P=0.00005;aRR:0.26,95%CI[0.12-0.57],P=0.0007).Conclusions:LBR per start cycle following PGT-A is significantly higher,and risk of miscarriage is significantly lower among infertile couples with RPL,irrespective of maternal age.PGT-A should be recommended to infertile couples with RPL.
基金Shanghai Shenkang Hospital Development Center Program(SHDC12017105).
文摘Objective:To evaluate the effect of preimplantation genetic testing for aneuploidy(PGT-A)in infertile patients with recurrent pregnancy loss(RPL).Methods:A prospective randomized clinical trial was performed in a university-affiliated fertility center in Shanghai,China.Patients in the PGT-A group underwent blastocyst biopsy followed by single-nucleotide polymorphism microarray-based PGT-A and single euploid blastocyst transfer,whereas patients in the control group underwent routine in vitro fertilization/ICSI procedures and frozen embryo transfer of 1-2 embryos selected according to morphological standards.Results:Two hundred and seven infertile patients with RPL were included in this study and randomly assigned to either the control or the PGT-A group.Baseline variables and cycle characteristics were comparable between the two groups.The results showed that PGT-A significantly improved the ongoing pregnancy rate(55.34%vs.29.81%)as well as the live birth rate(48.54%vs.27.88%)and significantly reduced the miscarriage rate(0.00%vs.14.42%)on a per-patient analysis.A significant increase in cumulative ongoing pregnancy rates over time was observed in the PGT-A group.Subgroup analysis showed that the significant benefit diminished for patients who attempted≥2 PGT-A cycles.Conclusions:PGT-A significantly improved the ongoing pregnancy and live birth rate,while reduced miscarriage rate in infertile RPL patients.However,the significance diminished in patients attempting≥2 cycles;thus,further studies are warranted to explore the most cost-effective number of attempts in these patients to avoid overuse.
文摘The first practice of pre-implantation genetic testing(PGT)was reported more than 30 years ago.PGT,originally named preimplantation genetic screening(PGS)and pre-implantation genetic diagnosis(PGD),is now categorized as PGT for aneuploidies(PGT-A),PGT for monogenic/single-gene defects(PGT-M),and PGT for chromosomal structural rearrangements(PGT-SR).Patients with fertility issues caused by advanced maternal age,carrier status of chromosomal abnormalities,or harboring pathogenic variant(s)are recommended to undergo PGT to increase the possibility of successful live birth and avoid potentially affected newborns.High-throughput techniques,such as DNA microarrays and next-generation sequencing(NGS),have enabled comprehensive screening of all 24 chromosomes,instead of few loci at a time.Furthermore,as a comprehensive PGT,PGT-Plus was enabled by the rapid development of a genome-wide single-cell haplotyping technique to detect embryo aneuploidy,single-gene disorders,and chromosomal aberrations simultaneously using a single universal protocol.In addition,non-invasive approaches enable a more intact embryo during the biopsy procedure,which may avoid potential mosaicism issues at a certain scale by testing spent culture media(SCM).As a novel PGT application,PGT-P detects genome-wide variations in polygenic diseases,which account for a large proportion of premature human deaths and affect a markedly larger population than monogenic diseases,using polygenic risk score calculation to decrease the potential of affecting complex conditions.Owing to the emergence of new technologies recruited to PGTs,more couples with infertility issues have a promising chance of conceiving a healthy baby,ultimately facilitating the human species to live more prosper.
基金supported by the Science and Technology Innovation Action Plan Program of Shanghai(18411953800)Shanghai Municipal Health Commission(20194Y0002).
文摘Preimplantation genetic testing(PGT)is an early form of prenatal genetic diagnosis,which can identify the abnormal embryos cultured in vitro,allow only transfer of genetically normal embryos,and improve the pregnancy rate.In recent years,the rapid development of microarrays and next-generation sequencing(NGS)technologies has remarkably accelerated the clinical application of PGT.In particular,a variety of detection methods have emerged and achieved significant progress in PGT for structural rearrangements(PGT-SR).The detection-related abilities of these methods range from the detection of limited chromosome aneuploidy to comprehensive chromosome screening of the whole genome to differentiation of embryos with normal or balanced translocation/inversion karyotypes.In this study,we reviewed PGT-SR-related detection techniques to provide a better reference for clinical application and research.We have also discussed the potential development of novel techniques in the future.
