Genetic Disease Screening PDF

Screening for Genetic Diseases Screening for genetic diseases is a method to identify individuals who may be at high risk for a genetic disease. The aim is to prevent or reduce the risk of the disease using different intervention strategies that depend on each disease....

Screening for Genetic Diseases Screening for genetic diseases is a method to identify individuals who may be at high risk for a genetic disease. The aim is to prevent or reduce the risk of the disease using different intervention strategies that depend on each disease. Prevent or reduce the Screening Intervention risk Population Individule at high risk Screening for Genetic Diseases Screening for genetic diseases can be through direct or indirect testing: Direct testing Detection of DNA mutation through DNA sequencing. Indirect testing Detection of biochemical changes through different laboratory assays. Screening for Genetic Diseases The screening can be A. Targeted to certain individuals Those with a positive family history of a specific genetic disease (e.g., carrier for an autosomal recessive disease) Those with a specific condition that increases their risk (e.g., Down syndrome with maternal age). B. General Population Is a large-scale testing offered to all individuals in a population for early identification of individuals who might have or develop a disease (e.g., newborn screening) Screening for Genetic Diseases Genetic screening Individuals at high risk Population screening based on Family history Increase the risk for Independent of any prior risk e.g., carrier for an autosomal certain condition recessive disease e.g., Newborn screening e.g., Down syndrome with maternal age ? ? Affected with AR disease ? ? ? Screening for Genetic Diseases Types of Genetic Screening Carrier testing for AR and X-linked Pre-symptomatic for AD Newborn screening Prenatal screening Carrier testing for AR and X-linked Carrier testing can identify people who are carriers of autosomal recessive disorders (or X-linked disorders in females). It can be done before or during pregnancy. It allows couples at risk to make informed decisions about having children. Carrier testing for AR and X-linked 0 % risk for 0 % risk for Healthy affected Healthy affected child child Carrier Affected Carrier 25% risk for affected What options are child avaible in this case? Carrier Carrier testing for AR and X-linked It is an effective tool to reduce the risk for common autosomal recessive disorders in populations 40 For example # of births with Tay-Sachs 35 30 - Carrier screening for Tay-Sachs disease in disease 25 Ashkenazi Jews significantly reduced the 20 incidence rate of the disease 15 10 5 0 1970 1975 1980 1985 1990 1995 2000 2005 - β-thalassemia disease in Greece and Italy reduced the incidence rate by ~75% Medical genetics 4th edition by Jorde et al. p. 262 Carrier testing for AR and X-linked In Saudi Arabia, the Saudi Premarital Screening Program started on 1425H, 2004. The program started with two genetic diseases that are common in the population: Sickle cell anemia and Thalassemia*. The premarital screening aims to give medical consultation on the odds of transmitting the diseases to the children and to allow better planning for a healthy family. * The AIDS and hepatitis B and C were added to the program as infectious diseases Carrier testing for AR and X-linked Carrier testing for AR and X-linked % of Cancelled Marriages Among at-risk Couples for Sickle cell or beta thalassemia in KSA 60% 50% Percentage of Marriages 40% 30% 20% 10% 0% 2004 2005 2006 2007 2008 2009 Years Memish et.al., Ann Saudi Med 2011; 31(3): 229-235 Carrier testing for AR and X-linked Results of the pre-marital screening Healthy Carrier Carrier Healthy Low risk Healthy Affected Affected Healthy Carrier Available Not to proceed options with the marriage High risk PGD Carrier Pre-symptomatic for AD Pre-symptomatic for AD Some single-gene diseases inherited as autosomal dominant have a delayed onset (e.g., the disease phenotypes appear in adulthood). For such conditions, a screening test can identify whether the person has inherited the mutation before developing the symptoms. Eligibility is for those who have a family member with the disease. Examples: Hereditary Breast and Ovarian Cancer syndrome (HBOC) Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Huntington Disease Pre-symptomatic for AD Example 1 Hereditary Breast and Ovarian Cancer syndrome (HBOC) Germline mutations in BRCA1 or BRCA2 (BRCA1/2) are found in 3% to 4% of all women with breast cancer which significantly increases risk for breast and ovarian cancer (see table) DNA variant in: Pre-symptomatic Symptomatic BRCA1 or BRCA2 Early detection and prevention 90% reduction in risk2 Gene Breast Ovarian Cancer risk1 Cancer risk1 BRCA1 80% 50% BRCA2 50% 30% 1-Nature Reviews Cancer. 2012 Jan;12(1):68–78. 2-JAMA. 2010 Sep 1;304(9):967–75. Pre-symptomatic for AD Example 1 Hereditary Breast and Ovarian Cancer syndrome (HBOC) Inherited as AD 25% Risk to 2nd degree relatives Risk to 1st degree relatives 50% 12.5% Risk to 3rd degree relatives Affected with breast cancer due to genetic mutation Pre-symptomatic for AD Example 2 Hereditary Non-Polyposis Colorectal Cancer (HNPCC) HNPCC or Lynch Syndrome is a condition that increases the risk to different cancers. ~ 3% to 5% of colorectal cancer cases are due to Lynch Syndrome. 20-80% risk for Colorectal Cancer DNA variant in: MLHL, MSH2, MSH6, PMS2, and EPCAM Early detection Reduction in risk Pre-symptomatic for AD Example 2 Hereditary Non-Polyposis Colorectal Cancer (HNPCC) Inherited as AD 25% Risk to 2nd degree relatives Risk to 1st degree relatives 50% 12.5% Risk to 3rd degree relatives Affected with colon cancer due to genetic mutation Pre-symptomatic for AD Example 3 Huntington Disease (HD) HD is a fetal neurodegenerative disease with adult-onset (> 40 years of age) No effective treatment to delay or treat the disease yet. The value of testing is not clear and depends on the person at risk (ethical concerns?). 100% risk of developing the disease > 40 years of DNA variant in: age HTT gene Early detection No intervention to ?? reduce the risk Preimplantation genetic diagnosis (PGD) Preimplantation genetic diagnosis (PGD) Carriers for autosomal recessive or X-linked or those with who have a disease-causing mutation can use Preimplantation genetic diagnosis (PGD) to reduce the risk of having an affected child. Preimplantation genetic diagnosis (PGD) is a medical procedure in which a few cells are removed from an embryo that is created using in vitro fertilization (IVF). The cells are then tested for genetic abnormalities, such as single-gene disorders or chromosomal problems. Only embryos that are free of the genetic abnormality are then implanted in the uterus. It is a complex and expensive procedure. There are some risks associated with PGD, such as the risk of miscarriage or birth defects. Preimplantation genetic diagnosis (PGD) In vitro Pre-implantation genetic test (PGD) fertilization Isolate a cell for diagnostic testing (e.g., check for the mutation of interest) ✓ Possible gametes for Proceed with individules who are implentation heterozygous for a disease- causing mutation ✗ Terminate Preimplantation genetic diagnosis (PGD) Optional slide for the PGD steps Nature Reviews Neurology volume 10, pages 417–424 (2014) Preimplantation genetic diagnosis (PGD) The PGD is avaible in KSA Newborn screening Newborn screening The newborn screening program screens all babies for conditions that could be life-threatening if not treated early Example of screening programs is screening for metabolic disorders in neonates (Inborn Errors of Metabolisms (IEM)). IEM disorders are genetic disorders that affect how the body breaks down and uses food. Newborn screening IEM disorders are caused by defects in enzymes, which help the body metabolize food. When an enzyme is defective, it can't break down a particular metabolite, which can lead to a buildup of toxic substances in the body. Normal metabolic pathway A loss of function Abnormal metabolic pathway mutation in gene B Gene A Gene B Gene C Enzyme B is not Gene A Gene B Gene C produced Enzyme A Enzyme B Enzyme C Enzyme A Enzyme B Enzyme C (a) Compound 1 Compound 2 Compound 3 Compound 4 (b) Compound 1 Compound 2 Compound 3 Compound 4 not synthesized not synthesized Accumulates compound 2 Newborn screening If an IEM disorder is not diagnosed and treated early, it can be fatal. There is no cure for IEM disorders, but there are treatments that can help manage the symptoms and prevent complications. Early diagnosis and treatment are essential for a good outcome. Treatment may include: Dietary restrictions Medications Gene therapy (experimental) Newborn screening The incidence rate of IEM in KSA is up to 1:10431 The Newborn Screening Program established in 1426H (2005) It started with 20 disorders including Congenital Hypothyroidism, Phenylketonuria, Galactosemia and 1- Alfadhel et al. J Paediatr Child Health. 2017 Jun;53(6):585-591. doi: 10.1111/jpc.13469 2- Saudi Med J. 2020 Jul; 41(7): 703–708. Newborn screening Newborn screening The screening is done by collecting a small blood sample from the baby's heel no earlier than 24-48 hours after birth. The baby must have an oral feeding. The blood is collected on a special filter paper that is then sent to a laboratory for testing. Prenatal screening Prenatal screening Prenatal screening is a group of tests that are done during pregnancy to check for certain health conditions in the fetus. It is recommended to couples who have the following indications: Advanced maternal age Previous child with a chromosomal abnormality Family history of a chromosome abnormality Family history of a single-gene disorder Family history of congenital structural abnormalities or undiagnosed learning disabilities. Prenatal screening Prenatal tests that allow testing the fetal DNA can be classified into: Invasive Non-invasive Prenatal screening Invasive tests Invasive tests involve taking a sample of tissue or fluid from the fetus. This can be done through a needle inserted through the mother's abdomen (amniocentesis), through the cervix (chorionic villus sampling), or through the umbilical cord (percutaneous umbilical blood sampling). Prenatal screening Invasive tests Amniocentesis Chorionic Villus Sampling Percutaneous umbilical blood (CVS) sampling (PUBS) Performed at 10-11 weeks Typically performed at 15-17 Performed at 18 weeks or later Risk of miscarriage of.05% to 1% weeks in pregnancy Risk of miscarriage as low as 1-2% risk for miscarriage about 1:600 Prenatal screening Non-invasive tests Non-invasive prenatal testing (NIPT) do not involve any contact with the fetus. Instead, it uses a sample of the mother's blood to look for fetal DNA (cell free DNA). Small amount of fetal cell-free DNA reach the maternal circulation from the placenta. This DNA can be used for genetic analysis. NIPT manly used for chromosomal abnormalities (Down syndrome, trisomy 18 and trisomy 13). NIPT is not a diagnostic test. Positive results need to be confirmed with invasive tests. Prenatal screening Non-invasive tests Prenatal screening Invasive vs. Non-invasive tests Feature Invasive Prenatal Tests Non-invasive Prenatal Tests Accuracy More accurate Less accurate Safety Less safe More safe Does not involve contact with Invasiveness Involves contact with the fetus the fetus Population screening criteria Criteria for a screening program at the population level Disease High incidence in target population In Saudi Arabia Serious effect on health Treatable or preventable The Pre-maraital screening program in KSA target Sickle cell aneamia and thalassemia Both diseases are seroius, relativly common Test and can be prevented. Non-invasive and easly carried out Non-invasive, inexpensive and accurate test Accurate and reliable that detect Sickle cell and thalassemia is Inexpensive available. Program Widespread and equitable availability Voluntary participation Acceptable to the target population Full information and councelling provided p. 148 reference book Ethical Considerations The four preiciples of Medical ethics are Autonomy Incorporate respect for the individual, privacy, informed consent, and confidentiality. Beneficence seeking to do good Non-maleficence seeking not to harm. Justice fairness for the patient in terms of resources, access and opportunity Ethical Considerations A difficulty in genetic testing can be the principle of autonomy, given that genes are shared with biological realtives. For example: For a pre-sympotomatic disease, a positive test results in an individule can have a major impact on close reltives who may not wish to know their disease status. Ethical Considerations Consider the following scenario for the implications of pre-symptomatic testing for Huntington disease on immediate family members: "A young man, age 20, requests a pre-symptomatic test (predictive test) for Huntington's disease before starting his family, knowing that his 65-year-old paternal grandfather is affected by the disease. However, his father is still free of any symptoms of the disease. Since the grandfather is affected, the father is at 50% risk of being a carrier. In this case, the father clearly does not wish to know if he will develop the disease (has the mutation). The young man's request raised the difficult question of how to honor his request without unintentionally carrying out a predictive test for his father. A positive result directly infers that the father has the mutation." Ethical Considerations Due to the sensitivity of the genetic data, they are protected by the Personal Data Protection Law in the kingdom.