INFERTILITY GENETIC TESTING. Dr. Ahmad Ebrahimi Molecular Medical Genetics,PhD Yass Medical Genetics Lab. Tehran University of Medical Science
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1 INFERTILITY GENETIC TESTING Dr. Ahmad Ebrahimi Molecular Medical Genetics,PhD Yass Medical Genetics Lab. Tehran University of Medical Science
2 INFERTILITY GENETIC TESTING It is estimated that genetics are a contributing factor in up to about 15% of male and 10% of female including Chromosome aberrations and Single gene mutations. who experience Infertility Recurrent pregnancy loss So it stands to reason that genetic testing has the potential to help many of those couples in their quest to have a family.
3 GENETIC SCREENING FOR INFERTILITY: WHEN SHOULD IT BE DONE? Diagnosis Treatment Prognosis & Outcome
4 First Step: Genetic Counselling & Background Risks Calculations Background risk Classification Differential Diagnosis Counselling for treatment or ART
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8 GUIDELINES FOR THE APPROPRIATE USE OF GENETIC TESTS IN INFERTILE COUPLES Sperm DNA Fragmentation Assay Karyotype analysis Micro deletions of the long arm of the Y chromosome CFTR gene Fragile X syndrome KAL1 gene-kallmann syndrome Monogenic Genetic Clotting Disorder/ Thrombophilia
9 GENETIC TESTS IN MALE INFERTILITY
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13 GUIDELINES FOR THE APPROPRIATE USE OF GENETIC TESTS IN INFERTILE COUPLES Sperm DNA Fragmentation Assay Karyotype analysis Micro deletions of the long arm of the Y chromosome CFTR gene Fragile X syndrome KAL1 gene-kallmann syndrome Monogenic Disorders Genetic Clotting Disorder/ Thrombophilia
14 MICRODELETIONS OF THE LONG ARM OF THE Y CHROMOSOME Yq micro deletion screening is strongly recommended during the diagnostic workup or prior to any ART procedure of infertile patients with sperm concentration is lower than 10 million/ml Non obstructive azoospermia Severe oligozoospermia suggestive physical features (e.g. small testicle size) Abnormal Karyotype Complete deletions of AZFa or AZFb are always associated with azoospermia. In general, TESE is possible in patients with AZFc deletions with a probability of recovering sperm of about 50%, but no in AZFa or AZFb deletions.
15 GUIDELINES FOR THE APPROPRIATE USE OF GENETIC TESTS IN INFERTILE COUPLES Sperm DNA Fragmentation Assay Karyotype analysis Micro deletions of the long arm of the Y chromosome CFTR Gene Mutation Analysis Fragile X syndrome KAL1 gene-kallmann syndrome Monogenic Genetic Clotting Disorder/ Thrombophilia
16 CFTR GENE Screening for CFTR mutations (including the 5T allele) is strongly recommended in infertile individuals with a diagnosis of bilateral or unilateral congenital absence of vas deferens (CBAVD or CUAVD). Mutations in the CFTR gene have not been unequivocally associated with reduced female infertility. However, women affected by cystic fibrosis are subfertile and have a higher risk of complicated pregnancy. The prevalence of the CFTR mutation in the general population (1 : 25), and the higher probability of a CFTR mutation to occur in the male partners of ICSI couples, recommend this test in the female partners candidate to ART.
17 Kallmann syndrome is rare and mutation analysis is not easily available, the Committee has recommended screening in all azoospermic men with hypogonadotropic hypogonadism (HH) characterized by low sex steroid and low gonadotropin levelsa nd anosmia. Kallmann syndrome should be suspected, and gene analysis performed, only in women with HH. KAL1 GENE-KALLMANN SYNDROME
18 ANDROGEN RECEPTOR GENE The Committee has suggested this test in azoospermic and severely oligozoospermic men with high androgen sensitivity index (ASI) In these cases the test should be performed as a second step, following karyotype analysis. Obviously, when other clinical manifestations of androgen insensitivity are present, the AR gene should be screened for mutations.
19 GENETIC TESTS IN FEMALE INFERTILITY
20 FRAGILE X SYNDROME This test is strongly recommended during the diagnostic workup of women with oligo-amenorrhoea caused by primary ovarian dysfunction (including preamture ovarian failure, POF) especially when ART is considered. A careful genetic counselling should be offered to patients carrying premutation and candidate to ART.
21 GENETICS OF FEMALE INFERTILITY Polycystic ovary syndrome (PCOS) is a complex and heterogeneous endocrine condition that affects 5% 10% of women. Gonadal Dysgenesis Premature Ovarian Failure Endometriosis only for prognostic aims Myomoma only for prognostic aims
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23 RARE SYNDROMES
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27 GUIDELINES FOR GENETIC INFERTILITY
28 REFERENCES Genetic Causes of Miscarriage. (2015). Retrieved from: Patural, A. (2007). Lower Your Miscarriage Risk With New Tests and Treatments. Retrieved from: Danielsson, K. (2016). Parental Karyotype Tests For Recurrent Miscarriage. Retrieved from: Repeated Miscarriages: FAQS. (2016). The American College of Obstetricians and Gynecologists. Retrieved from: Thrombophilias. (2016). Retrieved from: Clotting Disorders and Recurrent Miscarriage. (2016). Retrieved from: Jeve, Y. and Davies, W. (2014, July-Sept.). Evidence-Based Management of Recurrent Miscarriage. Journal of Human Reproductive Sciences, 7: Retrieved from: Rodriguez, H. (n.d.). 5 Steps To Decreasing the Chance of Recurrent Miscarriages. Retrieved from: Barton-Schuster, D. (2016). Defective MTHFR Gene Linked To Fertility and Pregnancy Struggles. Retrieved from:
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