Paediatric Genetics Flashcards
The gene for Huntington’s Chorea is a dominant gene and the gene for Cystic Fibrosis is a recessive gene.
I want to illustrate one final scenario for autosomal recessive conditions that is popular in exams as it is quite good at tricking the student so pay close attention. It is usually something like this: both parents are healthy, one sibling has a single gene disease (e.g. cystic fibrosis) disease, a second child does not have the disease, what is the likelihood of the second child being a carrier. We know that the condition is autosomal recessive, because it is impossible to inherit an autosomal dominant condition without having an affected parent. Both parents must be carriers because two abnormal copies are required for the first child to have the disease and if one parent had two abnormal copies they would also have the disease. Therefore the possible outcomes in future children are the same as in the first example above:
Outcome 1 has two abnormal copies and therefore has the condition.
Outcome 2 has one abnormal copy and one normal copy, therefore becomes a carrier.
Outcome 3 has one abnormal copy and one normal copy, therefore becomes a carrier.
Outcome 4 has two normal copies and therefore is neither has the disease or is a carrier.
So the risk of a future child being a carrier is 2 in 4, or 50%. However this is NOT the answer to the question as we know that the second child in the question does not have the phenotype of the disease, therefore we can exclude Outcome 1. Therefore, the possible genetic outcomes for the second child are 2, 3, or 4, and two of these outcomes (3 and 4) are that the child is a carrier. Therefore the risk of the second child being a carrier is 2 in 3.
Chromosome Disorders
Chromosome disorders are condition where there is either a structural abnormality, an extra abnormal portion or an abnormal number of chromosomes compared to normal.
Deletion
Deletion disorders occur where a portion of a chromosome is missing. These syndromes are very rare and you are unlikely to come across them, particularly in medical school exams. One example is cri du chat, which is caused by a missing portion of chromosome 5. Patients have learning, developmental and speech and language difficulties and a characteristic “cat like cry” as infants.
Duplication
Duplication disorders occur where a portion of a chromosome is duplicated. The chromosome contains twice the number of copies of that gene. One example is Charcot-Marie-Tooth, which can be caused by a duplication of the short arm of chromosome 17. Patients suffer with sensory and motor neuropathy and have characteristic pes cavus (high arching foot).
Translocation
Translocation disorders occur where a portion of one chromosome is directly swapped with a portion of another chromosome. The swap can be balanced (reciprocal translocations), where a portion of one chromosome is swapped with a portion of another. Alternatively they can be unbalanced (nonreciprocal translocations), where a portion of one chromosome leaves the first chromosome and attaches to the other without any exchange taking place.
Translocation does not usually lead to a specific genetic syndrome, but often predisposes to other conditions such as cancer and infertility. One example is the “Philadelphia chromosome” translocation in acute myeloid leukaemia, which is a reciprocal translocation between chromosome 9 and chromosome 22.
Robertsonian translocations occur in acrocentric chromosomes. These chromosomes are 13, 14, 15, 21 and 22. They have a longer long arm, which contains most of the genetic material, and a very short short arm with very little genetic information on it. When a person has a Robertsonian translocation, they loose the short arm completely, and the two long arms connect to each other at the centromere, essentially loosing a chromosome when they get rid of the two short arms. In this scenario the person is usually phenotypically normal, but has 45 chromosomes when counted and has a risk of problems in their offspring.
Trisomy
Trisomy is where the person has an extra chromosome. They have a total of 47 chromosomes. They have three copies of a particular chromosome. There are three conditions worth knowing about for your exams:
Patau syndrome: This is trisomy 13. The syndrome varies in severity. Patients have dysmorphic features, structural abnormalities affecting almost all areas of their body and learning disability. They have characteristic “rocker bottom feet”, where the soles of the feet are convex (rounded outwards) in shape. Look out for rocker bottom feet in exams.
Edwards syndrome: This is trisomy 18. The syndrome varies in severity and affects almost all areas of the body, resulting in dysmorphic features and learning disability. They also have “rocker bottom feet”.
Down’s syndrome: This is trisomy 21. This is the most common trisomy condition. See the full section on Down’s.
Mosaicism
Mosaicism is an interesting scenario where the chromosomal abnormality actually happens after conception. The abnormality occurs in a portion of cells in the body and not in others. The person therefore has different genetic material in different cells in their body. Each case is unique and the effects are unpredictable.
Mitochondrial Inheritance
At the time of conception, the sperm carrying the fathers genetic material enters the egg and the DNA in the nucleus of both cells combine. The vast majority of the mitochondria in that first cell (called the zygote) come from the mother. All of the mitochondria in the sperm are in the tail, which does not enter the egg. Therefore, the father does not contribute any mitochondria to the zygote and subsequently the fetus and child. Therefore, mitochondrial DNA is primarily from the mother. This is called maternal inheritance.
If we are looking at a specific disease gene in the mitochondria DNA, we need to consider that not all mitochondria within the mothers cells will be affected. The proportion of affected mitochondria that are passed to the offspring will determine whether that individual is affected.
Genetic testing
Diagnostic Testing
Diagnostic testing involves testing a fetus or a person for a suspected genetic condition. We can test a fetus for a genetic condition via amniocentesis. An example of this is antenatal testing for Down’s syndrome. Antenatal testing can have implications on the decision to continue the pregnancy. Where a specific condition is suspected, for example Turner syndrome, it is possible to test directly for that condition in a child or adult.
Predictive Testing
Predictive testing involves testing a person for a specific gene mutation that has implications for them in the future. Examples are the BRCA1 breast cancer gene or the gene for Huntington’s chorea.
Carrier Testing
Carrier testing involves testing parents or potential parents for the gene for a specific autosomal recessive condition in order to calculate the risk of passing it to their children. An example of this is testing for the cystic fibrosis gene.
Other Specific Scenarios
Genealogical testing
Forensic testing
Paternity testing
Ethical issues of genetic testing
There are significant ethical implications for genetic testing. It is essential to get consent and perform some level of genetic counselling before doing the test, and discuss the implications of the result. The greater the implications of the test, the more genetic counselling will be required.
For example, if a patient’s parent suffered with Huntington’s chorea, there is a 50% chance they have the gene and will inevitably develop the same highly disabling condition. Having a test that tells you whether or not you will definitely develop this condition is very different to getting a simply cholesterol check. It is important that the person is fully informed about the implications of the results, not only for them but also their family.
Karyotyping
Karyotyping involves looking at the number of chromosomes, their size and basic structure. This is helpful in diagnosing conditions like Down’s syndrome (trisomy 21) and Turner syndrome (45 XO).
Microarray Testing
Microarray testing involves cutting up the genetic material from an individual using enzymes. Different genes will have different molecular weights. The chopped up genetic material is then applied to a plate that separates molecules of different weights into different locations. This can be used to see what genes the person expresses. For example, if you know that the gene for cystic fibrosis is a certain size, and when this gene is chopped out and applied to the plate it ends up in a specific location on the plate, you can test an individual to see whether they have a clump of molecules at that location. If they do, this suggests they are expressing that gene.
This has many applications, such as screening for chromosomal abnormalities and many common genetic conditions, looking for mutations in cancer cells and also for research aimed at matching genes with phenotypes.
Specific gene testing
Specific gene testing can be done by splitting the two strands of DNA and adding a “gene probe”. The gene probe is made of single stranded DNA that contains complementary genetic code for a specific gene you want to test for. When the strands of DNA are mixed with the gene probe and the gene probe matches the genetic material on the DNA, they will stick together. This suggests the specific gene that matches the gene probe is present. This is used to confirm whether a patient has a particular gene.
DNA Sequencing
DNA sequencing is only used for research purposes, and has no role in routine clinical practice. This involves splitting the two strands of DNA and watching as individual nucleotides are added to a single strand of DNA, ultimately revealing the exact sequence of nucleotides in that section of DNA.
Down’s Syndrome
Down’s Syndrome is caused by three copies of chromosome 21. It is also called trisomy 21. It gives characteristic dysmorphic features and is associated with a number of associated conditions. The extent to which the person is affected and the associated conditions they have vary between individuals.
Dysmorphic Features of Down’s Syndrome
Hypotonia (reduced muscle tone)
Brachycephaly (small head with a flat back)
Short neck
Short stature
Flattened face and nose
Prominent epicanthic folds
Upward sloping palpebral fissures
Single palmar crease
Epicanthic folds are folds of skin covering the medial portion of the eye and eyelid. The palpebral fissures are the gaps between the lower and upper eyelid.
Complications of Down’s Syndrome
Learning disability
Recurrent otitis media
Deafness. Eustachian tube abnormalities lead to glue ear and conductive hearing loss.
Visual problems such myopia, strabismus and cataracts
Hypothyroidism occurs in 10 – 20%
Cardiac defects affect 1 in 3, particularly ASD, VSD, patent ductus arteriosus and tetralogy of Fallot
Atlantoaxial instability
Leukaemia is more common in children with Down’s
Dementia is more common in adults with Down’s
Antenatal Screening for Down’s Syndrome
All women are offered screening for Down’s syndrome. The purpose of the screening test is to decide which women should receive more invasive tests that would give a definitive diagnosis.
It is the choice of the woman whether to go ahead with screening. The screening tests involve taking measurements from the fetus using ultrasound, combining those measurements with the mothers age and blood results and providing an indication of the risk of Downs syndrome. Older mothers have a greater risk of Down’s syndrome.
Combined Test
The combined test is the first line, most accurate and test of choice where possible. This test is performed between 11 and 14 weeks gestation. It involves combining results from ultrasound and maternal blood tests.
Ultrasound measures nuchal translucency, which is the thickness of the back of the neck of the fetus. Down’s syndrome is one cause of a nuchal thickness over 6mm.
Maternal blood tests:
Beta‑human chorionic gonadotrophin (beta-HCG). A higher result indicates a greater risk.
Pregnancy‑associated plasma protein‑A (PAPPA). A lower result indicates a greater risk.
Triple Test
The triple test is performed between 14 and 20 weeks gestation. It only involves maternal blood test results:
Beta-HCG. A higher result indicates greater risk.
Alpha-fetoprotein (AFP). A lower result indicates a greater risk.
Serum oestriol (female sex hormone). A lower result indicates a greater risk.
Quadruple Test
The quadruple test is performed between 14 and 20 weeks gestation. It is identical to the triple test but also includes maternal blood for inhibin-A. A higher inhibin-A indicates a greater risk.
Antenatal Testing for Downs Syndrome
The screening tests provide a risk score for the fetus having Down’s syndrome. When the risk of Down’s is greater than 1 in 150 (this result occurs in around 5% of tested women) the woman is offered amniocentesis or chorionic villus sampling. These tests involve taking a sample of the fetal cells, which then undergo karyotyping to give a definitive answer to whether the fetus is affected by Down’s or not.
Chorionic villus sampling (CVS) involves an ultrasound guided biopsy of the placental tissue. This is used when testing is done earlier in pregnancy (before 15 weeks).
Amniocentesis involves ultrasound guided aspiration of some amniotic fluid using a needle and syringe. This is later in pregnancy once there is enough amniotic fluid to make it safer to take a sample.
