Recently, there is also growing evidence on the implication of TPE in various human diseases [ ]. Animal studies have shown that ART procedures may be associated with multiple alterations in gene expression and DNA methylation, mainly of imprinted genes [ ]. However, the potential relationship with phenotypic outcomes if any remains largely unknown. Also in human studies, epigenetic alterations associated with ART have been reported in embryos and placental tissue or umbilical cord blood [ ].
However, these alternations have not yet been unambiguously associated with any clinically relevant outcomes, thus far. Future studies should focus on the normal epigenetic regulation in human gametes and embryos, the natural inter-individual variation in, for example, DNA methylation, the consequences of slight alterations in DNA methylation and phenotypical long-term consequences of epimutations [ ]. Recently it was suggested that there is inter-individual variation in susceptibility to environmentally mediated epigenetic alterations in humans [ ].
Furthermore, the environmentally induced epimutations occur possibly on a stochastic basis [ ] making 'one-to-one' associations between an environmental clue and epigenetic alterations at a specific gene or set of genes less informative. This observation might also explain inconsistencies found between various studies. ART-induced epigenetic alterations, if they exist, might thus occur at random places in the genome, in only a subset of vulnerable subjects, probably leading to a wide range of adverse phenotypic consequences, which would complicate research on the potential epigenetic effects of ART [ ].
Finally, it needs to be noted that these follow-up studies are also hampered by common parental unwillingness to disclose previous IVF treatments, including data security concerns regarding relevant patient registries. The panel concluded that more research is needed on the potential impact of specific ART procedures on the epigenome and its consequences for the offspring, including possible epigenetic inheritance pathways. Furthermore, relevant social and ethical issues related to this issue need to be explored. Genome editing using tools allowing for exact modification, such as zinc-finger nucleases and TALENs transcription activator-like effector nucleases , have been available for many years and have been widely used in research [ ].
GGE can be performed in different germ cell types, such as spermatogonial stem cells, in vitro matured oocytes, stem cell-derived gametes differentiated in vitro from pluripotent stem cell lines obtained after somatic cell nuclear transfer or induced pluripotent stem cells, and even in the early embryo [ , ]. GGE at the embryo level has important technical drawbacks, such as incomplete editing leading to mosaic embryos and off-target effects induced disease-associated variants at sites other than the intended on-target site that need to be solved before considering possible clinical applications of the technique.
As newer, more accurate, efficient, and therefore safer GGE systems are being developed, it is to be expected that these technical limitations could be overcome [ ] as was recently documented in the case of hypertrophic cardiomyopathy [ ]. Nevertheless, the number of clinical indications that could be envisaged for GGE remediation is limited, thus far, since PGT-M offers an alternative for couples at risk for a genetic disease in their offspring.
The potential use of GGE could be envisioned in very high-risk couples, for example, if one partner is homozygous for an AD disease, or when both partners suffer from the same AR disorder. Less 'stringent' indications could be in cases where the number of embryos expected to be obtained after PGT-M is small, for example, in case of advanced maternal age, or couples at high risk for transmitting more than one genetic disease, or when HLA-matching embryos considered for curing a sibling affected by a severe monogenic disease.
Other medical fields also started to discuss the potential implications of GGE [ ]. Furthermore, there is an ongoing debate on the ethical i. Finally, a transparent and broad collaboration is necessary in order to move the field of GGE responsibly forward [ , ]. The panel concluded that although research in the field of GGE is rapidly developing, its potential medical applications within the context of ART and genetic medicine require further basic and translational research.
Consensus guidelines need to be developed by respective professional societies, which will take into account any potentially adverse individual-, population genetic-, ethical- and societal implications of this novel medical technology. The intersection of ART and genomics is a fast growing scientific field, both from the basic and translational research points of view. A selected portfolio of emerging topics was included in the agenda for the third panel meeting, mainly covering issues, which have the highest potential of entering, or that are already part of, current clinical practice.
As molecular genetic techniques are improved, complete characterisation of the entire human genome variation of an embryo might become a reality. Together with the emergence of therapeutic possibilities comprising, for example, mitochondrial transfer and GGE, professional and ethical discussions around these developments need to be undertaken and international recommendations drawn up in order to determine how such novel technologies ought to be implemented in ART practice in a responsible and evidence-based manner, and accordingly regulated. The panel looks forward to the fourth meeting to discuss these ongoing developments at a European level in the near future.
This paper is the report of a meeting of experts from around Europe to assess how the latest developments in genetics might impact on assisted reproduction. Their discussion included testing for genetic diseases for people wanting to get pregnant and the growth of commercial genetic testing, which may mean that anonymity for people who have donated eggs or sperm cannot be guaranteed.
They also considered advances in identifying genetic factors in both male and female infertility and in genetic testing or screening of embryos. They discussed early pregnancy screening and techniques involving mitochondria as well as the impact of IVF on the way genes might work and new techniques for editing, or altering, genes. They concluded that developments in genetics are increasingly relevant in the fertility field as some new techniques are already being used in clinics.
They called for international recommendations to consider how new technologies should be introduced into the field of assisted reproduction. Current issues in medically assisted reproduction and genetics in Europe: research, clinical practice, ethics, legal issues and policyeuropean society of human genetics and european society of human reproduction and embryology. Eur J Hum Genet.
The interface between assisted reproductive technologies and genetics: technical, social, ethical and legal issues. Calhaz-Jorge C, de Geyter C, et al. Hum Reprod. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY challenge.
Genome Biol. Committee Opinion No. Obstet Gynecol ;e35— Expanded carrier screening in reproductive medicine—points to consider. Obstet Gynecol. Responsible implementation of expanded carrier screening. Eur J Hum Genet ;e1— NGS-based assay for the identification of individuals carrying recessive genetic mutations in reproductive medicine. Hum Mutat. Preconceptional genetic carrier testing and the commercial offer directly-to-consumers. Cystic fibrosis carrier screening effects on birth prevalence and newborn screening.
Genet Med. Attitudes of european geneticists regarding expanded carrier screening. J Obstet Gynecol neonatal Nurs. Intrafamilial medically assisted reproduction. Hum Reprod ;26 3 — Factors for successful implementation of population-based expanded carrier screening: learning from existing initiatives. Eur J Public Health. New insights into the generation and role of de novo mutations in health and disease.
The effect of parental age on the presence of de novo mutations - Lessons from neurofibromatosis type I. Mol Genet genomic Med. Whole-genome sequencing in newborn screening? A statement on the continued importance of targeted approaches in newborn screening programmes. Eur J Hum Genet ;— Accessed 14 Sep Influence of individual differences in disease perception on consumer response to direct-to-consumer genomic testing. Clin Genet. El-Hazmi MAF. Ethics of genetic counseling - basic concepts and relevance to Islamic communities. Saudi Med. Eur J Endocrinol. Simpson JL, Rechitsky S.
Preimplantation diagnosis and other modern methods for prenatal diagnosis. J Steroid Biochem Mol Biol. Somatic mosaicism: implications for disease and transmission genetics. Trends Genet. Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet. Parent psychological adjustment, donor conception and disclosure: a follow-up over 10 years. Attitudes and disclosure decisions of Finnish parents with children conceived using donor sperm.
The end of donor anonymity: how genetic testing is likely to drive anonymous gamete donation out of business. Adopting genetics: motivations and outcomes of personal genomic testing in adult adoptees. Zadeh S.
Disclosure of donor conception in the era of non-anonymity: safeguarding and promoting the interests of donor-conceived individuals? Abbott A. Genetic tests obtainable through pharmacies: the good, the bad, and the ugly. Hum Genomics. Anonymity 2. Fertil Steril. Millbank J. Med Law Rev. Female infertility, infertility-associated diagnoses, and comorbidities: a review. J Assist Reprod Genet. Genetics of male infertility: from research to clinic. Ankolkar M, Balasinor NH. Endocrine control of epigenetic mechanisms in male reproduction.
Horm Mol Biol Clin Investig. Paternal age explains a major portion of de novo germline mutation rate variability in healthy individuals. PLoS One. Causes of male infertility: a 9-year prospective monocentre study on patients with reduced total sperm counts. Cell Tissue Res. Accessed 20 Apr Reproductive tract microbiome in assisted reproductive technologies. Hotaling J, Carrell DT. Clinical genetic testing for male factor infertility: current applications and future directions.
Aston KI. Genetic susceptibility to male infertility: news from genome-wide association studies. Mol Hum Reprod. Identification of a new recurrent aurora kinase C mutation in both European and African men with macrozoospermia. Exome sequencing reveals a nonsense mutation in TEX15 causing spermatogenic failure in a Turkish family.
Hum Mol Genet. X-Linked T EX11 mutations, meiotic arrest, and azoospermia in infertile men. N Engl J Med. Targeted next generation sequencing approach identifies eighteen new candidate genes in normosmic hypogonadotropic hypogonadism and kallmann syndrome. Mol Cell Endocrinol. Deregulation of sertoli and leydig cells function in patients with Klinefelter syndrome as evidenced by testis transcriptome analysis. BMC Genomics. RASopathies: presentation at the genome, interactome, and phenome levels. Mol Syndromol.
Novel mutation of RUNX2 gene in a patient with cleidocranial dysplasia. Int J Clin Exp Pathol. Liu T, Huang J. DNA end resection: facts and mechanisms. Genomics Proteomics Bioinformatics. New clinical and molecular insights into silver—russell syndrome. Curr Opin Pediatr. Whole-exome sequencing and targeted copy number analysis in primary ciliary dyskinesia. G3 Bethesda. Laissue P. Aetiological coding sequence variants in non-syndromic premature ovarian failure: From genetic linkage analysis to next generation sequencing.
Genetics of the ovarian reserve. Front Genet. Yatsenko SA, Rajkovic A. Chromosomal causes of infertility: the story continues. In: Sermon K, Viville S, editors. Textbook of Human Reproductive Genetics. Cambridge: Cambridge University Press; Premature ovarian insufficiency: new perspectives on genetic cause and phenotypic spectrum.
Endocr Rev. Genes and infertility. Cambridge: Cambridge University Press; ; p. Trends Endocrinol Metab. Phenotype and tissue expression as a function of genetic risk in polycystic ovary syndrome. Epigenetic alterations affecting transcription factors and signaling pathways in stromal cells of endometriosis. Genetics of primary ovarian insufficiency. Genetics of primary ovarian insufficiency: new developments and opportunities. Hum Reprod Update. Identification of multiple gene mutations accounts for a new genetic architecture of primary ovarian insufficiency.
J Clin Endocrinol Metab. Mutant cohesin in premature ovarian failure. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. Primary ovarian insufficiency collaboration. Laven J. Genetics of early and normal menopause. Semin Reprod Med. Genetics of mitochondrial dysfunction and infertility. Expanding the genotypic spectrum of Perrault syndrome.
Clin Genet ;— Mutations in TUBB8 cause a multiplicity of phenotypes in human oocytes and early embryos. J Med Genet. TLE6 mutation causes the earliest known human embryonic lethality. Effect of follicle-stimulating hormone receptor AsnSer polymorphism on the outcomes of controlled ovarian hyperstimulation: an updated meta-analysis of 16 cohort studies. Epub Oct Are F SHR polymorphisms risk factors to premature ovarian insufficiency?
How Science and Genetics are Reshaping the Race Debate of the 21st Century - Science in the News
Fertil Steril ; 3 — Epub Jul Traeger-Synodinos J. Pre-implantation genetic diagnosis. Geraedts J, Sermon K. Preimplantation genetic screening 2. Comprehensive chromosome screening improves embryo selection: a meta-analysis. Open versus closed systems for vitrification of human oocytes and embryos. Reprod Biomed Online. Optimal euploid embryo transfer strategy, fresh versus frozen, after preimplantation genetic screening with next generation sequencing: a randomized controlled trial.
Fertil Steril ;—e3. Developments in IVF warrant the adoption of new performance indicators for ART clinics, but do not justify the abandonment of patient-centred measures. Live birth after PGD with confirmation by a comprehensive approach karyomapping for simultaneous detection of monogenic and chromosomal disorders. Genome-wide karyomapping accurately identifies the inheritance of single-gene defects in human preimplantation embryos in vitro. Karyomapping-a comprehensive means of simultaneous monogenic and cytogenetic PGD: comparison with standard approaches in real time for Marfan syndrome.
Concurrent whole-genome haplotyping and copy-number profiling of single cells. Application of next-generation sequencing for chromosome aneuploidy screening of human preimplantation embryos. Mol Cytogenet. The why, the how and the when of PGS 2. Prenatal and pre-implantation genetic diagnosis. Nat Rev Genet ;— Dynamics and ethics of comprehensive preimplantation genetic testing: a review of the challenges.
Van den Veyver IB. Recent advances in prenatal genetic screening and testing. Accreditation of the PGD laboratory. Do we pay enough attention to culture conditions in context of perinatal outcome after in vitro fertilization? Biomed Res Int. Guidelines for diagnostic next-generation sequencing. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the american college of medical genetics and genomics and the association for molecular pathology.
Recommendations for reporting results of diagnostic genetic testing biochemical, cytogenetic and molecular genetic. Next-generation sequencing in oncology: genetic diagnosis, risk prediction and cancer classification.
Int J Mol Sci. Fragouli E, Wells D. Aneuploidy in the human blastocyst. Cytogenet Genome Res. Scott RT, Galliano D. The challenge of embryonic mosaicism in preimplantation genetic screening. Healthy babies after intrauterine transfer of mosaic aneuploid blastocysts. Albertini DF, Gleicher N. A detour in the quest for oogonial stem cells: methods matter. Nat Med. Why do euploid embryos miscarry? A case-control study comparing the rate of aneuploidy within presumed euploid embryos that resulted in miscarriage or live birth using next-generation sequencing.
Advanced maternal age patients benefit from preimplantation genetic diagnosis of aneuploidy. Preimplantation genetic screening PGS still in search of a clinical application: a systematic review. Reprod Biol Endocrinol. Intent to treat analysis of in vitro fertilization and preimplantation genetic screening versus expectant management in patients with recurrent pregnancy loss. Gleicher N, Orvieto R. Is the hypothesis of preimplantation genetic screening PGS still supportable?
A review. J Ovarian Res. Blastocentesis: a source of DNA for preimplantation genetic testing. Results from a pilot study. Preimplantation genetic testing: polar bodies, blastomeres, trophectoderm cells, or blastocoelic fluid? Molecular analysis of DNA in blastocoele fluid using next-generation sequencing. Blastocoele re-expansion time in vitrified-warmed cycles is a strong predictor of clinical pregnancy outcome. J Obstet Gynaecol Res. Extracellular embryo genomic DNA and its potential for genotyping applications.
Futur Sci OA. Characterizing nuclear and mitochondrial DNA in spent embryo culture media: genetic contamination identified. Presence of fetal DNA in maternal plasma and serum. In: A dvances in clinical chemistry. Cytogenetic confirmation of a positive NIPT result: evidence-based choice between chorionic villus sampling and amniocentesis depending on chromosome aberration. Expert Rev Mol Diagn. Cell-free fetal DNA testing for prenatal diagnosis. Adv Clin Chem. Prenat Diagn. Noninvasive prenatal screening for fetal aneuploidy, update: a position statement of the American College of Medical Genetics and Genomics.
NSGC practice guideline: prenatal screening and diagnostic testing options for chromosome aneuploidy. J Genet Couns. J Matern Fetal Neonatal Med. Global perspectives on clinical adoption of NIPT. Non-invasive prenatal diagnosis in the management of preimplantation genetic diagnosis pregnancies. J Clin Med. Non-invasive prenatal testing for aneuploidy and beyond: challenges of responsible innovation in prenatal screening. Nuffield Council on Bioethics. Non-invasive prenatal testing: ethical issues.
Next generation sequencing and the next generation: how genomics is revolutionizing reproduction. Prenat Diagn ;— Noninvasive detection of fetal trisomy systematic review and report of quality and outcomes of diagnostic accuracy studies performed between and J Med Screen. Analysis of cell-free DNA in maternal blood in screening for aneuploidies: updated meta-analysis. Ultrasound Obstet Gynecol. Cell-free DNA analysis for noninvasive examination of trisomy. Accuracy of non-invasive prenatal testing using cell-free DNA for detection of Down, Edwards and Patau syndromes: a systematic review and meta-analysis.
BMJ Open ;6:e Reflex antenatal DNA screening for Down syndrome. Clinical implementation of routine screening for fetal trisomies in the UKNHS: cell-free DNA test contingent on results from first-trimester combined test. BMC Pregnancy Childbirth. Noninvasive prenataltesting - when is it advantageous to apply? Biomed Hub. Presymptomatic identification of cancers in pregnant women during noninvasive prenatal testing.
JAMA Oncol. Noninvasive prenatal testing and incidental detection of occult maternal malignancies. Cell-free DNA as a diagnostic marker for cancer: current insights. Onco Targets Ther. Contingent non-invasive prenatal testing: an opportunity to improve non-genetic aspects of fetal aneuploidy screening. Potential diagnostic consequences of applying non-invasive prenatal testing: population-based study from a country with existing first-trimester screening. Nuchal translucency measurement in the era of prenatal screening for aneuploidy using cell free cf DNA.
The clinical utility of DNA-based screening for fetal aneuploidy by primary obstetrical care providers in the general pregnancy population. Benn P. Expanding non-invasive prenatal testing beyond chromosomes 21, 18, 13, X and Y. Fetal sex determination from maternal plasma in pregnancies at risk for congenital adrenal hyperplasia. Clinical application of fetal sex determination using cell-free fetal DNA in pregnant carriers of X-linked genetic disorders. J Hum Genet. Prenatal whole genome sequencing: just because we can, should we?
Hastings Cent Rep. For your interest? Fetal therapy for Down syndrome: an ethical exploration. Evolutionary defined role of the mitochondrial DNA in fertility, disease and ageing. Concise reviews: Assisted reproductive technologies to prevent transmission of mitochondrial DNA disease. Stem Cells. PGD and heteroplasmic mitochondrial DNA point mutations: a systematic review estimating the chance of healthy offspring.
Mitochondrial transfer: Implications for assisted reproductive technologies. Appl Transl Genomics. Mitochondrial replacement therapy in reproductive medicine. Trends Mol Med. McGrath J, Solter D. Nuclear transplantation in the mouse embryo by microsurgery and cell fusion.
Advances in Human Genetics
Towards clinical application of pronuclear transfer to prevent mitochondrial DNA disease. Mitochondrial gene replacement in primate offspring and embryonic stem cells. Human embryonic stem cells derived by somatic cell nuclear transfer. Cell ;— Towards germline gene therapy of inherited mitochondrial diseases. Live birth derived from oocyte spindle transfer to prevent mitochondrial disease. Pregnancy derived from human zygote pronuclear transfer in a patient who had arrested embryos after IVF. Polar body transfer restores the developmental potential of oocytes to blastocyst stage in a case of repeated embryo fragmentation.
Ethics of mitochondrial replacement techniques: a habermasian perspective. Novel techniques for the prevention of mitochondrial DNA disorders: an ethical review - Bredenoord AL, Hyun I. The road to mitochondrial gene transfer: follow the middle lane. Mol Ther ;—6. Am J Stem Cells.
Mitochondrial modification techniques and ethical issues. Cytoplasmic transfer in assisted reproduction. Oocyte formation by mitotically active germ cells purified from ovaries of reproductive-age women. Regulation of injury-induced ovarian regeneration by activation of oogonial stem cells. Mitochondrial DNA content as a viability score in human euploid embryos: less is better. Mitochondrial DNA assessment to determine oocyte and embryo viability. Accurate quantitation of mitochondrial DNA reveals uniform levels in human blastocysts irrespective of ploidy, age, or implantation potential.
John JC. Mitochondrial DNA copy number and replication in reprogramming and differentiation. Semin Cell Dev Biol. Mitochondrial DNA in Day 3 embryo culture medium is a novel, non-invasive biomarker of blastocyst potential and implantation outcome. Analysis of gene-specific and genome-wide sperm DNA methylation.
Methods Mol Biol ;— Reprogramming DNA methylation in the mammalian life cycle: building and breaking epigenetic barriers. DNA methylation dynamics of the human preimplantation embryo. Kelsey G, Feil R. New insights into establishment and maintenance of DNA methylation imprints in mammals. Smallwood SA, Kelsey G. De novo DNA methylation: a germ cell perspective. Trends Genet ;— The Embryo and Its Future1.
Biol Reprod. Feil R, Fraga MF. Epigenetics and the environment: emerging patterns and implications. Nat Rev Genet. Distinctive chromatin in human sperm packages genes for embryo development. Advances in Human Genetics pp Cite as. The adrenal cortex produces three principal categories of steroid hormones that regulate a wide variety of physiologic processes from fetal to adult life. Mineralocorticoids , principally aldosterone, regulate renal sodium retention and thus profoundly influence electrolyte balance, intravascular volume, and blood pressure.
Glucocorticoids , principally Cortisol, are named for their carbohydrate-mobilizing activity, but are ubiquitous physiologic regulators influencing a wide variety of bodily functions. Adrenal androgens serve no essential physiologic role, but do mediate some secondary sexual characteristics in females, and their overproduction may result in virilism. These biologically active steroids are synthesized from cholesterol by the complex series of enzymatic conversions summarized in Fig.
The molecular biology of steroid hormone synthesis has been reviewed in detail recently Miller, a; Strauss and Miller, , and thus is only outlined briefly here. Genetic disorders exist for each of the steps in steroid hormone synthesis. To understand the phenotypic, clinical manifestations of each of these disorders it is important to understand the steroidogenic pathways and the enzymes that mediate steroid hormone synthesis.
Unable to display preview. Download preview PDF. Skip to main content. Advertisement Hide. This process is experimental and the keywords may be updated as the learning algorithm improves. This is a preview of subscription content, log in to check access. Al-Othman, A. PubMed Google Scholar. Amor, M. USA 82 : — USA 85 : — Aston, C. Baltimore, D. Baron, J. The role of the iron-sulfur protein, adrenodoxin in mixed function oxidation reactions, Arch. Belt, K. Besman, M. USA 86 : — Google Scholar.
Black, S. Areas Mol. Biol 60 : 35— Brentano, S. Bristow, J.
Brown, M. Cara, J. Carroll, M. Casey, M. Steroid Biochem.
Chanderbhan, R. Chang, C. Chaplin, D. USA 83 : — Chetkowski, R. Chiou, S. Chrousos, G. Chua, S. USA 84 : — Chung, B. Collier, S. Conneely, O. USA — Davidson, J. Dawkins, R. DiBlasio, A. Donohoue, P. Dumic, M. Dunham, I. Dupont, B. Terasaki, ed. Duque, C. Egel, R. Ehlen, T. Fiet, J. Fincham, J. Fleischnick, E. Forest, M. Frasier, S. Garlepp, M. Geffrotin, C. Giles, C. Gitelman, S. Globerman, H. Gnanaiah, W. Goebelsmann, U. Golos, T. Gonzalez, F. Gourmelen, M. Gwynne, J. Haglund-Stengler, B. Hanukoglu, I. Harada, F. Hauffa, B. Hauptmann, G. Higashi, Y. Tokyo : — Holler, W.
Hood, L. Hu, M. Hughes, I. Jackson, J. Jefcoate, C. Jospe, N. Kay, P. Kimura, T. Kochhan, L. Kohn, B. Kominami, S. Kutten, F. Kwok, S. Lambeth, J. Levine, L.