Preconception & Genetic Counselling PDF

PBL 1 + L2—› Preconception + genetic counselling Anatomy of the female reproductive system–› no doc de anatomia Patterns of inheritance Preconception advice (do´s and don’ts) ○ Lifestyle and risk factors ○ Medication- change it? Stop it? Start it? How long can she start trying?...

PBL 1 + L2—› Preconception + genetic counselling Anatomy of the female reproductive system–› no doc de anatomia Patterns of inheritance Preconception advice (do´s and don’ts) ○ Lifestyle and risk factors ○ Medication- change it? Stop it? Start it? How long can she start trying? ○ (How can drugs interfere) Genetic testing Facilities of preconception period Why does and anencephaly happen? ——————————————————————————————————————————————————————— Preconception De nition The total of education and care that can or should be given around conception for the health of the mother and child Who and where? - Primary care–› responsibility of the GP; Health centers, where family planning consultations are free - Secondary tertiary care: gynecologist, obstetricians, clinical geneticist, neurologist, cardiologist, etc Aim: To identify and modify medical, behavioral or environmental risks to female or male reproductive health and future pregnancies. During this consultation: The clinician should obtain informations to establish the risk of reproductive abnormality and propose measures to minimise that risk Clinical history: assess the medical condition of the woman/couple- to review medication use and safety of use evaluate their family history- family tree, consanguinity, genetic diseases ○ by a clinical geneticist Chronic diseases: Heart disease, diabetes, rheumatoid arthritis, thyroid disease, hypertension, epilepsy, tuberculosis, asthma, mental diseases (to evauate medication) General data: Evaluations of weight, height, BMI, blood pressure, pulse rate Analysis: Check hemoglobin (anemia), blood group and Rh factor, screen of hemoglobinopathies, fasting glycemia, screen for syphilis, HIV, toxoplasmosis, thyroid function, hepatitis B, rubella, cytomegalovirus (vaccination if applicable) Vaccinations: Assessment of vaccination status and update according to PNV (priority against tetanus, diphtheria, rubella and measles) If applicable: hepatitis B, cytomegalovirus, rubella and COVID-19. Supplements: Folic acid, 400 µg/day. If there is an increased risk for having a child with a neural tube defect (5mg/day) Iode,150 µg/day Iron, 30-60 mg/day fi Common chronic medical conditions that affect pregnancy Smoking – estimated to account for 20 to 30% of low-birth-weight babies, up to 14 % of preterm deliveries, and about 10% of all infant deaths according to the American Lung Association. Drinking Alcohol – There is no safe amount of alcohol to consume while you are pregnant. Recreational Drug Use – Recreational Drug Use during pregnancy can increase the chance of miscarriage, low birth- weight, premature births, developmental delays, and behavioral and learning problems. Prescription Drugs – There are many prescription drugs that are teratogenic (cause birth defects). Hazardous Chemicals – There are some chemicals that can also be teratogenic. For example, most studies show that the greatest risk of exposure to pesticides is during the rst three to eight weeks of the rst trimester when the neural tube development is occurring. This is often before a woman knows she is pregnant. Stress – Stress has been linked to delayed or missed periods which can cause dif culty tracking ovulation and getting pregnant. Limit your amount of stress as much as possible. Herbs – Most herbs and herbal remedies are not mandated by the FDA, and therefore, there is little to no research on the effect they have on pregnancy. Discuss any herbal or natural remedies you may be used with your healthcare provider. Caffeine – Some studies have shown a link between high levels of caffeine consumption and delayed conception. A few studies have shown that there may be an increase in miscarriages among women who consume more than 200 mg (one 12oz cup of coffee) a day versus those who do not consume any caffeine. Teratogenic medications Screen both partners for use of teratogenic medications (see also “Pharmacotherapy during pregnancy”). Make medication adjustments before discontinuing contraception. ○ Consider changing to safer medication, reducing the dose, or, if safe, stopping the medication. ○ Consult a specialist if there are no safe alternatives or the medication should not be stopped. Dietary recommendations, including: ○ Vitamin and mineral supplementation in pregnancy, including: ◆ Initiating prenatal folate supplementation at least 1 month before conception ◆ Suf cient intake of other micronutrients (e.g., calcium, iron, vitamin B12, vitamin B9, vitamin D) ○ Dietary restrictions during pregnancy, e.g., reduced intake of seafood with potentially high levels of mercury Recommend 150 minutes of moderate-intensity exercise or 75 minutes of vigorous activity per week. fi fi  Genetic counselling De nition: A process that gives information regarding the risk of developing a genetic condition, or transmitting a genetic condition to the next generation, as well as management advice, and family planning in order to prevent or avoid it Aim: To help individuals, couples and families understand the genetic contribution to speci c health and to help people to make informed decisions related to genetic testing and reproductive choices. → usually carried out by a clinical geneticist Reasons that a person might be referred to a clinical geneticist include: A personal or family history of a known or suspected genetic disorder A child with a known inherited disorder, a birth defect, intellectual disability, or developmental delay 2 or more pregnancy losses (miscarriages), a stillbirth, or neonatal loss with structural anomalies A woman who is pregnant or plans to become pregnant at ≥ age 35 Consanguinity (blood relationship of parents, rst cousins, or closer) Fetal structural anomaly on prenatal ultrasound that suggest a genetic or chromosomal condition This process integrates the following : Interpretation of family and medical histories to assess the chance of disease occurrence or recurrence Education about the natural history of the condition, inheritance pattern, testing, management, prevention, support resources and research Counselling to promote informed choices in view of risk assessment, family goals, ethical and religious values Support to encourage the best possible adjustment to the disorder in an affected family member and/or to the risk of recurrence of that disorder Family tree/pedigree Represent family members and relationships using standardized symbols It is a way of analyzing the inheritance patterns of a trait within a family It shows about what happened in the past and also what might happen in the future Genetic diseases Abnormalities in the genome Types: Mendelian Multifactorial/polygenic diseases Mitochondrial diseases (only from mother) Chromosomal diseases Expansion repeat diseases– trinucleotide repeat disorder Mendelian diseases Results from a single defective gene. Inherited in recognizable patterns, according to the Mendel’s laws fi fi  e Patterns of inheritance REMEMBER!!!: gene-eye color-allelleegie eg green : Allleles—› different versions of the same gene E.g: blue eye color or green eye color are both alleles for the same gene–› eye color gene They can be dominant (A) or recessive (a). ≠ is that it only takes one dominant allele for the trait to be expressed and 2 of the recessive for the trait to be expressed During fertilisation the alleles combine: Homozygous dominant (AA) Homozygous recessive (aa) Heterozygous (Aa) Mutation on somatic chromosome–› autosomal inheritance Mutation on sex chromosome—› sexual inheritance X linked ot Y linked Autosomal Dominant - An on AA 1 mutant copy causes the disease Each affected person has an affected parent Occurs in every generation Have the disease: DD or Dd Dominanta DD–› rarely reproduce because the disease is to severe Usually a person with the disease has: 1 affected grandparent Affected and non affected uncles and aunts 1 affected parent Affected and non affected siblings E.g: Huntingtons disease —› Mutation can appear spontaneously in a persons whose family isn’t affected Autosomal Recessive It takes 2 mutant copies to cause the disease Both parents of an affected person are carriers Not typically seen in every generation Only recessive homozygotes have the disease: rr Heterozygotes are carriers: Rr E.g: cystic brosis If you inherit 1 allele form each parent it means that both parents have to have a small r, meaning both are carriers. Usually a person with the disease has: Unaffected parents and grandparents Affected great grandparents fi Sex linked inheritance so tem 1 copia do gene · Men: 1 allele for the genes on X and Y chromosomes—› hemizygous Woman: 2 alleles on the X chromosome—› homozygous or heterozygous P X-linked Dominant Male : X Y Females more frequently affected Can have affected males and females in same generation Males only pass the mutant allele to daughters Female : XPXP XP yd Females pass the mutant allele to sons and daughters E.g: fragile X syndrome X-linked Recessive Males more frequently affected Affected males often present in each generation Males can’t be carriers E.G: hemophila Y linked passed from father to son Mitochondrial Can affect both males and females, but only passed on by females Can appear in every generation Examples lecture Case 1–› Cystic brosis –› Autosomal recessive disease We must understand who has it, how it was discovered, what is your relation to this person, and if you are pregnant - CF is a disease that affects different organs: lung infections, enlarged heart, gallstones - Prevalence: 1:2500 Cause More than 1000 mutations identi ed in CF in the CFTR gene located at chr. 7q31 Clinical Features chronic and usually progressive symptoms often start at birth and involve the lungs and gastrointestinal tract thick secretions and chronic infections in the lung, lead to bronchiectasis Gene function Encodes a transmembrane protein acting as a channel across the membrane of cells that produce mucus, sweat, saliva, tears, and digestive enzymes. When the channel function is impaired, it causes high salt content sweat, and highly viscous mucus secretions Both parents are carriers. Risk of having a child with CF is 25% Case 2–› Intellectual disability- fragile X –› X linked recessive disease Epidemiology the most common cause of inherited intellectual disability affects approximately 1 in 2500-4000 males and 1 in 7000-8000 Clinical Features mild to severe intellectual de cit It may be associated with behavioural disorders and characteristic physical features including a high forehead, prominent and large ears, at feet hyperextensible nger joints Molecular basis: Caused by a CGG repeat expansion in the 5’UTR of FMR1 gene, located on Xq27.3 Genetic test The genetic testing involve the determination of the number of repeats CGG Normal range: 4-44 Intermediate range: 45-199 Expansion range: >200 fl fi fi fi fi  In the affected individual, the size of the repeats CGGs in the FMR1 gene is the Normal range: 4-44 Carriers in orange, affected in blue. The affected X chromosome is passed on from the mother to the daughters and sons. Males only have 1 X chromosome rather than 2 like women to counteract the affected chromosome. The female which has the pointed arrow has no risk of having a kid with Fragile-X because her father is not affected, and her parents aren’t affected Case 3–› Consanguinity First cousins: 1/8 identical genes Higher risk for autosomal recessive disorders First cousins: preconception carrier screening in USA (2021) A protocol for 1st cousins screening of consanguineous couples using NGS (“Next Generation Sequencing”) Coding parts of all (~20.000) genes: ‘exome—› Complete DNA: ‘genome’ Group of genes instead of 1 by 1 Whole Exome Sequencing (WES) in both partners Do they both carry a mutation in the same gene? In that case: 25% chance of a child with that genetic condition Preconception care and Genetic counseling Making a reproductive choice Choices: 1. Spontaneous pregnancy and accept the risk, no intervention 2. Spontaneous pregnancy and prenatal testing 3. Preimplantation Genetic Test (PGT) 4. No children 5. Adoption 6. Donor egg/sperm Preimplantation Genetic Test (PGT) Only for couples at high risk of transmitting a known genetic condition to their offspring IVF followed by selection of embryo’s without the mutation or chromosomal abnormality 20% chance of pregnancy per treatment Max. of 3 treatments; overall chance of 50% Smoking, overweight and advanced maternal age diminish the chance of pregnancy It takes place in a reference centre by a team of experts in gynecology/obstetrics, embryology, and medical genetics In 2006, it was created a law (Lei n.º 32/2006, de 26 de julho; “Procriação medicamente assistida”, Medically Assisted Procreation to regulate this procedure >100 diseases are considered by the “Conselho Nacional de Procriação Medicamente Assistida” as severe genetic diseases in which the most frequent ones are: -Fragile-X, Machado-Joseph disease, Huntingon disease, Down syndrome and Paramyloidosis Ethical issues - All these procedures: preconception care, genetic counseling, PGT, raised a lot of ethical concerns and challenges - Is it ethical to design a child to be born free of abnormalities? Anencephaly: How It Happens Anencephaly is a severe congenital condition categorized under neural tube defects (NTDs). It arises due to improper closure of the neural tube during early embryonic development, speci cally between the third and fourth week of gestation. Below is an in-depth explanation of the process: Neural Tube Formation The neural tube, a structure forming the brain and spinal cord, begins as a at layer of cells (neural plate). The neural plate folds and fuses, starting from the middle and extending to the ends (cranial and caudal). In anencephaly, the cranial end (head region) of the neural tube fails to close. This disruption leaves the developing brain and skull exposed to amniotic uid. Cellular and Molecular Factors Genetic Factors: Mutations in genes regulating neural tube closure (e.g., MTHFR, VANGL1) may impair this process. Nutritional De ciencies: Insuf cient folate (Vitamin B9) is a critical factor. Folate supports DNA synthesis and cell division, essential for neural development. Environmental Triggers: Exposure to teratogens (e.g., alcohol, certain medications) or uncontrolled maternal diabetes can disrupt neural tube formation. This leads to absence of Brain Structures: The cerebral hemispheres (responsible for cognition and voluntary actions) and overlying skull bones are either absent or severely underdeveloped. The exposed neural tissue degenerates in the amniotic environment, preventing normal brain function. fi fi fl fi Risk Factors Maternal folate de ciency Family history of neural tube defects Maternal obesity or diabetes Preventive Measures: Adequate folic acid supplementation (400–800 µg daily) before conception and during early pregnancy can reduce the risk by up to 70%. fi