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The Genetic Risk of a Couple Aiming to Conceive
Published in Carlos Simón, Carmen Rubio, Handbook of Genetic Diagnostic Technologies in Reproductive Medicine, 2022
Joe Leigh Simpson, Svetlana Rechitsky, Anver Kuliev
An individual presenting for infertility treatment is usually assumed to have no heritable condition, but this must be confirmed. An ostensibly healthy but infertile adult may actually have features indicating mild expression of a single-gene disorder. Irrespective of mild severity (expressivity), these individuals may have a mutant gene that is potentially transmissible to offspring. A chromosomal disorder may be recognized for the first time at infertility consultation, for example 47, XXY Klinefelter syndrome having azoospermia. A male with congenital bilateral absence of vas deferens (CBAVD) may have a pathogenic variant of the cystic fibrosis gene. He may have one ΔF508 allele and one abnormal 5T allele. If the clinically unaffected partner is heterozygous for ΔF508, the risk of homozygous ΔF508 cystic fibrosis in the offspring is one in four.
Assessment of fetal genetic disorders
Published in Hung N. Winn, Frank A. Chervenak, Roberto Romero, Clinical Maternal-Fetal Medicine Online, 2021
Teresa Martino, J. Pratt Rossiter, Karin J. Blakemore
A family history of a single-gene disorder is another common indication for referral for prenatal genetic counseling. Fetal risk assessment is dependent on many factors, such as the distance of the relationship between the affected family member and the individual seeking counseling, as well as the frequency of the disease gene in the population. Couples with a previously affected child may be obviously at higher risk for recurrence, while the risk declines with increased distance from the affected relative (1°>2°>3°). For example, parents of a child with an autosomal recessive disorder have a 25% risk of recurrence with each pregnancy. By contrast, the offspring to the siblings of an affected individual have a risk calculated as follows: the risk of the unaffected sibling being a carrier (2/3), times the risk that the partner is a carrier (the population carrier frequency if the family history is negative), times the risk of having an affected offspring given that both parents are carriers (1/4). Thus, for cystic fibrosis, with a carrier frequency of 1 in 25 Caucasian Americans, the risk for an unaffected sibling of an affected individual to have an offspring with cystic fibrosis is 2/3×1/25×1/4 = 1/150. Carrier testing of the sibling, when available, may refine these odds.
Genetic Counseling for Preimplantation Genetic Testing
Published in Darren K. Griffin, Gary L. Harton, Preimplantation Genetic Testing, 2020
Lauri D. Black, Jill M. Fischer
Single-gene disorder cases are the most involved cases for the genetic counselor in the IVF clinic as well as the PGT laboratory given the complex case preparation. Once referred to the PGT laboratory for PGT-M, an intake will be completed by telephone with the patient. The intake includes thorough explanation of the case preparation process and timeline, testing technique, completion of medical and family histories inclusive of a pedigree, and review of appropriate genetic testing reports on necessary family members. If any necessary reports are not available, these will be requested, and results confirmed and received prior to test creation. If necessary, for family members who have not undergone testing, the PGT laboratory genetic counselor will work with the genetic counselor at the IVF center or a genetic counselor local to the family members to arrange for such testing. Once all the required reports are received and the case is approved by the genetic counselor and molecular teams, the test creation can proceed. The PGT laboratory genetic counselor then arranges for appropriate DNA samples to be sent to the laboratory. These can be blood, saliva, buccal swabs, or extracted DNA depending on the test technique and creation process. Should DNA be available from a deceased family member or previous pregnancy, the genetic counselor arranges for it to be sent to the PGT laboratory. The PGT laboratory genetic counselor provides updates to the patient and IVF center throughout the test creation process.
The importance and implications of preconception genetic testing for accurate fetal risk estimation in 21-hydroxylase congenital adrenal hyperplasia (CAH)
Published in Gynecological Endocrinology, 2019
Suresh Rama Chandran, Lih Ming Loh
Preimplantation genetic diagnosis (PGD) is the genetic testing conducted on the early stage embryos before transfer to the mother’s uterus during the course of in vitro fertilization (IVF) [20]. This is different from pre-implantation screening used during IVF to screen for aneuploidy, select embryos and increase the chances of a successful pregnancy. PGD can be used to sex the embryo, diagnose a single gene disorder or to identify chromosomal defects [20]. Genetic materials from an embryo can be obtained at various stages of its development; however, earlier stages increase the risk of damage to embryo and implantation failure while later stages may lead to attrition in the number of viable embryos [21]. Apart from these disadvantages, methodological errors can happen during amplification and hybridization of fetal DNA. This could lead to allele drop outs and wrong genetic diagnosis [21]. Hence, prior to embarking on a PGD and IVF, patients with CAH must be informed of the pitfalls of this technique as recommended by the European Society for Human Reproduction and Embryology consortium [22].
Cytogenetic analysis of patients with primary amenorrhea in Eastern India
Published in Journal of Obstetrics and Gynaecology, 2018
Shaulee Ghosh, Sanchita Roy, Pritha Pal, Atreyee Dutta, Ajanta Halder
WHO has estimated that amenorrhoea stands as the 6th commonest cause of female infertility. Additionally, among the general population amenorrhoea affects 2%–5% of all women of child bearing age. As indicated from several previous studies genetic abnormalities account for a major portion of primary amenorrhoea patients, which may be a single gene disorder/chromosomal or multifactorial. The reported percentage of chromosomal abnormalities vary greatly from 15.9 to 63.3%. This wide variation in the percentage is likely due to variation in the sample size, patient origin and also the selection criteria for the patients. Even in certain rural parts of India, many patients with sex-related abnormalities do not come for the medical advice considering it as a social stigma, thus the actual frequency of sex abnormalities in patients with amenorrhoea remains undetermined. In the present study the high percentage of chromosomal abnormalities (23.9%) detected in our patients is in accordance to the results obtained in several studies listed in Table 3 (Butnariu et al. 2011; Kalavathi et al. 2010; Kong H et al. 2007; Ramírez et al. 2000; Vijayalakshmi et al. 2010).
Interaction between Hb E and Hb Yala (HBB:c.129delT); a novel frameshift beta globin gene mutation, resulting in Hemoglobin E/β0 thalassemia
Published in Hematology, 2018
Supachai Ekwattanakit, Suchada Riolueang, Vip Viprakasit
However, this patient in our study had a relatively mild non-transfusion-dependent phenotype, suggesting a less severe pathobiology to globin synthesis. Using anin vitro model, this mutation was analyzed for its impact on mutated β-globin gene transcription and translation [28]. Consistently with a milder clinical phenotype in our patient, this nucleotide deletion caused a significant reduced mRNA probably due to non-sense mediated decay mechanism using a quantitative real-time polymerase chain reaction analysis. This suggests that an expected toxic truncated β-globin variant might not be generated leading to a less severe phenotype [28]. This mutation has been reported as a functional study before [28]; however, it is of interest to further describe clinical case presentation as a reference and a more detailed clinical history to provide further evidence that there is always a discrepancy between a functional cell and/or animal model and true clinical effects in human subjects. Such a difference highlights a complexity of genotype–phenotype correlation even within a so-called single-gene disorder, such as thalassemia.