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Reproductive genetics, Preimplantation genetic diagnosis 512 - Development Sterility is inability to conceive a child during one up to two years of frequent intercourse without the use of contraceptives Femal infertility (dysfertility) is inability to carry baby to term or give birth to viable baby with sustained ability to conceive Sterility Primary – women have not been pregnant yet Secondary - women were pregnant in the past Many pregnancies terminated earlier, than we can prove in conventional methods Sterility covers 15-20% of couples 33% of male fertility disorder 25% female fertility disorder 20% fertility disorders both in the pair 15% of unknown cause Abnormalities of chromosomes caused 30% of all abortions and 60% of early abortions Autosomal monosomy Gardner, Sutherland: Chromosome abnormalities and genetic counseling, 1996 Thrombophilic mutations cause infertility Mutations increasing the risk of clotting = thrombophilic mutations Factor V Leiden R506Q mutation – in the gene for coagulation factor V. It is manifested in homozygotes and heterozygotes = nature of AD mutations Factor II Protrombin G20210A mutation cause higher level of prothrombin. It is mutation of Caucasian race mutation MTHFR = reductase methylenetetrahydrofolate cause thrombophilic complications and neutral tube defects. nature of AR mutations Blood coagulation pathways in vivo Sterility causes - men Genetic causes For the 50% of sterile men is cause a quantitative or qualitative defect of spermatogenesis Autoimmunity to own sperm Epididymal Blockage Coital problems Vasectomy Varicocele An abnormal enlargement of the venous plexus in the scrotum. Investigative methods - men Urine, immunological, hormonal, psychological examination, genetic testing, biopsy epididymis/testis Spermiogram - volume, viscosity, pH, concentration sperm : 20mil/ml – normospermia Motility: moving quickly progressively........... a slow-moving progressively………….. b non-progressive moving ......... ……..c immobile..................................……….d Spermiogram Computer analysis - quantitative evaluation of mobility, analysis of the track and speed Normozoospermia Oligozoospermia less than 20mil/ml Asthenozoospermia less than 50% a+b or less than 25% a type Teratozoospermia less than 30% morphologically normal Azoospermia absence of sperm cells Aspermie absence of ejaculate Genetic cause - men An aneuploidy of X, Y, 21, 8, 18 chromosome is observed in sperms of the 70% of sterile men Chromosomal aberrations Marker chromosome Inversion, ring, deletion of Y chromosome Reciprocal translocation Y - autosome It was proved an increased incidence of abortions in the (woman) partner of carrier of balanced form of translocation Gene defects of Y chromosome Azoospermia factor AZF (AZFa, AZFb, AZFc) = genes in Yq12 and in Yq11 affected by mutations - deletions, microdeletions. Microdeletions are cause for 3,77% of sterile men and for 15,63% of azoospermic men Gene mutation Cystic fibrosis – 95% men with CF are sterile. 20% of asoospermic men suffer form CF Syndromes Klinefelter's syndrome Syndrome XYY- both fertile and sterile Women pseudohermafroditismus – 46 XX, translocation chromosome Y or the part (SRY gene) to another chromosome Androgen insensitivity syndrome complete - testicular feminization in 40% of men with oligospermia and azoospermia incomplete androgen resistance - XR hypospadias, cryptorchidism, micropenis Kartagener syndrome AR hypospadia Investigative methods - women Examination of passable fallopian tube, hormonal, immunological, psychological examination Ovulation: progesterone, basal temperature, endometrial sample examination, ultrasound examination Genetic: karyotype, fluorescence hybridization in situ Sterility causes - women Genetic causes Tubal blockage or damage Endometriosis - the presence of uterine mucosa in reproductive tissues Hormonal problems Too thick cervical mucus Immunological rejection of sperm Problems with zygote implantation Premature menopause Genetic - syndromes Turner syndrome - karyotype 45 X0, deletions X (Xp), mosaic forms of syndrome (50%). Woman with isochromosome (women with i Xq) are fertile. Karyotype 47, XXX Syndrome of polycystic ovarian Kallman syndrome - reduced function of glands producing sex hormones (absence of GnRH) Chromosomal aberration Polyploidy, aneuploidy in gametes especially of autosomes, reciprocal and Robertsonian translocation, Inversions, Marker chromosomes, Microdeletion syndromes Disorders of gonadal development - Autosomal and X- linked gene affected by mutations, which cause gonadal dysgenesis, hypogonadotropic hypogonadism - hormonal cause - mutation or aberation of SRY region - mutation of gene encoding DAX1 protein, which acts against the SRY product Complex structural rearrangement of chromosomes 3, 8, 10 – FISH, balanced form of karyotype in mother Microdeletion syndroms Current Protocols in Human Genetics Online Copyright © 2003 John Wiley & Sons, Inc. Postcoital test (Sims-Huhn) = test of lifetime of sperm cells: 6 - 24 hod after the intercourse is taken a sample of mucus from the cervix (uterus) More than 6 progressively moving sperms is normal situation Sterility treatment Women - pharmacological treatment of ovulation disorders Surgical treatment of tubal abnormalities Surgically or pharmacological treatment of Endometriosis Men - sperm changes - change in lifestyle!! pharmacological treatment Surgical treatment of varicocele or occlusion Pharmacological treatment of endocrine or immunological causes Assisted reproduction - methods IUI intrauterine insemination IVF in vitro fertilization ICSI intracytoplazmatic injection of sperm AH - assisted hatching ET – embryotransfer TESE - testicular extraction of sperm MESA - biopsy of epididymis PZD - parcial disection of zona pellucida SUZI - subzonal insemination - location of 1 to 7 sperm in perivitelinne space Kryokonzervation of gametes, embryos TESE, MESA PZD SUZI ICSI Embryotransfer IUI IUI artificial insemination after induction of ovulation are obtained and washed sperm cells of the husband or donor and are transferred into the uterus using a special catheter indications: women with hormonal disorders, men with the inability to ejaculate into vaginy In vitro fertilization – IVF = pharmacological stimulation of ovulation, the collection of several oocytes, cultivation in laboratory conditions with sperms, transfer of embryos into uterus indications: blockage of fallopian tubes, endometriosis, unknown cause Intracytoplazmatic injection of sperm - ICSI = pharmacological stimulation, micromanipulatory insemination, transfer of embryos into the uterus indications: defects in sperm, oligoasthenospermia, azoospermia (MESA, TESE), unsuccessful IVF Assisted hatching = disruption of zona pellucida, which contributes to increase the probability of embryo implantation in the uterine mucosa Indication: an unsuccessful pregnancy with IVF or in women over 35 years It is provided by chemical, mechanical, laser way. Preimplantation genetic diagnostics - PGD Molecular - genetic, molecular - cytogenetic examination of gametes, polar bodies, blastomeres, blastocyst Benefits = Reduced risk of spontaneous abortions Reduced number of children affected by chrom. aberrations Reduced number of affected children with a genetic mutation (AR, XR) Increased successful rate of implantation of embrya, of assisted reproduction methods Preconceptional genetic diagnostics Biopsy of polar bodies – Disadvantage: small amount of material DNA analysis of genome of mother only. Risk of crossing-over, which leads to a false pos and false neg results. Preimplantation genetic diagnostics Biopsy of blastomere 1-2 blastomeres are examined in 2-3 day after in vitro fertilization method: it is embryo of 6-10 blastomers Disadvantages: It is amplified the information only from one allele, thus there is the risk of mozaicism (1blastomer) Advantages: analysis of father and mother genome Biopsy of blastocyst for fertile couples advantages: analysis of the genome of father and mother, analysis of multiple cells of trofoblast, - 3-4 cells in 5. day after in vitro fertlilization method The optimal combination is an examination of both polar bodies with biopsy of blastomere and with the control of conclusions of prenatal diagnostics in II trimester Indication - PCR versus FISH PCR: AD gene mutations, AR gene mutations, gene mutations of male sterility FISH: aneuploidy, presence of translocation in one of parents, identification of sex in X-linked inherited diseases Monogenic hereditary disease Familial adenomatous polyposis of the colon - AD Deficiency of alpha-1-antitrypsin - AR Cystic fibrosis - AR Duchenne muscular dystrophy - XR Fragile X chromosome syndrome - XR Haemophilia A, B - XR Huntington's disease - AD Marfan Syndrome - AD Sickle cell anemia - AR Tay-Sachs disease - AR Thalassemia AR ............ mediterranean FISH MultiVysion (13,18,21,X,Y) MultiVysion (13,16,18,21,22, X,Y,15,17) (13,16,18,21,22) Z materiálu Dr. Jenčíkové - GENNET Trisomie 13,18,21,X Z materiálu Dr. Jenčíkové - GENNET Thank you for attention http://www.advancedfertility.com/hatching.htm Human Genetics, Ricki Lewis, chapter 21: Reproductive technologies