Genetics

Question 1

What is mosaicism?

Answer 1

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.

Question 2

What is predictive testing?

Answer 2

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.

Question 3

What is microassay testing?

Answer 3

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.

Question 4

What is specific gene testing?

Answer 4

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.

Question 5

What are the dysmorphic features in trisomy 21?

Answer 5

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

Question 6

Give three complications of trisomy 21

Answer 6

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

Question 7

What is the combined test?

Answer 7

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.

Question 8

What is the triple test for trisomy 21?

Answer 8

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.

Question 9

What is chorionic villus sampling?

Answer 9

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).

Question 10

What is amniocentesis?

Answer 10

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.

Question 11

What causes Klinefelter syndrome?

Answer 11

Klinefelter syndrome occurs when a male has an additional X chromosome, making them 47 XXY.

Question 12

How does Klinefelter syndrome present?

Answer 12

Usually patients with Kleinfelter syndrome appear as normal males until puberty. At puberty can develop features suggestive of the condition:

Taller height
Wider hips
Gynaecomastia
Weaker muscles
Small testicles
Reduced libido
Shyness
Infertility
Subtle learning difficulties (particularly affecting speech and language)

Question 13

How do we treat Klinefelter syndrome?

Answer 13

There is no way to treat the underlying genetic cause of Klinefelter syndrome. Treatment aims to help with the features of the condition:

Testosterone injections improve many of the symptoms
Advanced IVF techniques have the potential to allow fertility
Breast reduction surgery for cosmetic purposes
Multidisciplinary team input:

Speech and language therapy to improve speech and language
Occupational therapy to assist in day to day tasks
Physiotherapy to strengthen muscles and joints
Educational support where required for dyslexia and other learning difficulties

Question 14

What is Turner syndrome?

Answer 14

Turner syndrome occurs when a female has a single X chromosome, making them 45 XO. The O referrs to an empty space where the other X chromosome should be. Life expectancy is close to normal.

Question 15

How does Turner syndrome present?

Answer 15

The three classic features to remember and look out for in exams are short stature, webbed neck and widely spaced nipples.

Question 16

What is cubitus valgus?

Answer 16

Cubitus valgus refers to an abnormal feature of the elbow. When the arm is extended downwards with the palms facing forward, the angle of the forearm at the elbow is exaggerated, angled away from the body. Seen in Turner syndrome

Question 17

How do we treat Turner syndrome?

Answer 17

There is no way to treat the underlying genetic cause of Turner syndrome. Treatment aims to help with the symptoms of the condition:

Growth hormone therapy can be used to prevent short stature
Oestrogen and progesterone replacement can help establish female secondary sex characteristics, regulate the menstrual cycle and prevent osteoporosis
Fertility treatment can increase the chances of becoming pregnant

Question 18

What is Marfan syndrome?

Answer 18

Marfan syndrome is an autosomal dominant condition affecting the gene responsible for creating fibrillin. Fibrillin is an important component of connective tissue. This means people with Marfan syndrome have features resulting from abnormal connective tissue.

Question 19

How does Marfan syndrome present?

Answer 19

Tall stature
Long neck
Long limbs
Long fingers (arachnodactyly)
High arch palate
Hypermobility
Pectus carinatum or pectus excavatum
Downward sloping palpable fissures

Question 20

How do we test for arachnodactyly?

Answer 20

There are two tests for arachnodactyly to remember: First, ask them to cross their thumb across their palm, if the thumb tip goes past the opposite edge of the hand this indicates arachnodactyly. Next ask them to wrap the thumb and fingers of one hand around the other wrist, if the thumb and fingers overlap this also indicates arachnodactyly.

Question 21

What is the most important aspect of management in Marfan syndrome?

Answer 21

The greatest risk is from the associated cardiac complications, particularly valve prolapse and aortic aneurysms. Where these complications occur they may require surgical correction.

The aim of management is to minimise the blood pressure and heart rate to minimise the stress on the heart and the risk of complications developing. This is achieved by lifestyle changes, such as avoiding intense exercise and avoiding caffeine and other stimulants. Preventative medications such as beta blockers and angiotensin II receptor antagonists can also help reduce the risk of complications. Pregnancy has to be carefully considered, as it carries a significant risk of developing aortic aneurysms and associated complications.

Question 22

What is fragile X syndrome?

Answer 22

Fragile X syndrome is caused by a mutation in the FMR1 (fragile X mental retardation 1) gene on the X chromosome. The FMR1 gene codes for the fragile X mental retardation protein, which plays a role in cognitive development in the brain.

Question 23

How is fragile X syndrome transmitted?

Answer 23

It is X-linked, but it is unclear whether it is dominant or recessive. Males are always affected, but females can vary in how much they are affected. This is because females have a spare normal copy of the FMR1 gene on their other X chromosome. When the mother is phenotypically normal, the affected child may have inherited the X chromosome from their mother, or it may result from a de novo (random) mutation.

Question 24

How does fragile X syndrome present?

Answer 24

Fragile X syndrome usually presents with a delay in speech and language development. Other features are:

Intellectual disability
Long, narrow face
Large ears
Large testicles after puberty
Hypermobile joints (particularly in the hands)
Attention deficit hyperactivity disorder (ADHD)
Autism
Seizures

Question 25

What causes Prader-Willi syndrome?

Answer 25

Prader-Willi Syndrome is a genetic condition caused by the loss of functional genes on the proximal arm of the chromosome 15 inherited from the father. This can be due to a deletion of this portion of the chromosome, or when both copies of chromosome 15 are inherited from the mother.

Question 26

How does Prader-Willi syndrome present?

Answer 26

The key feature everyone remembers for Prader-Willi syndrome is the the insatiable hunger. Feeding can often be a challenge initially due to hypotonia and it is only later that the food seeking and excessive eating occur. It is worth remembering some other key facts about the condition, such as the treatment with growth hormone and the poor muscle tone, so that you know more than just the link with appetite.

Question 27

How do we manage Prader-Willi syndrome?

Answer 27

There is no cure. Carefully limiting access to food under guidance of a dietician is required to control weight. This usually requires locking food in cupboards, putting a lock on the fridge and even controlling access to rubbish bins. Under dietician guidance they usually require a lower than normal calorie intake, particularly as they tend to have lower activity levels due to poor muscle strength and tone. Everyone that is in contact with the child will need to be educated about limiting access to food, including teachers, carers and relatives.

Growth hormone is indicated by NICE as a treatment for Prader-Willi Syndrome, aimed at improving muscle development and body composition.

Question 28

What is Angelman syndrome/

Answer 28

Angelman syndrome is a genetic condition caused by loss of function of the UBE3A gene, specifically the copy of the gene that is inherited from the mother. This can be caused by a deletion on chromosome 15, a specific mutation in this gene or where two copies of chromosome 15 are contributed by the father, with no copy from the mother.

Question 29

How does Angelman syndrome present?

Answer 29

The novel features to remember and link with Angelman syndrome so you can spot it in your exams is the unusual fascination with water, happy demeanour and widely spaced teeth.

Question 30

What causes William syndrome?

Answer 30

William syndrome is caused by a deletion of genetic material on one copy of chromosome 7, resulting in the person only having a single copy of the genes on this deleted region (on the other chromosome 7). It usually the result of a random deletion around conception, rather than being inherited from an affected parent.

Question 31

How does William syndrome present/

Answer 31

The distinctive features to remember with William syndrome are the very sociable personality, the starburst eyes, ADHD and the wide mouth with a big smile. It is worth remembering the association with supravalvular aortic stenosis and hypercalcaemia, as these are unique features that are easy to test in exams.

Question 32

How do we manage William syndrome?

Answer 32

Like many other genetic syndromes, there is no cure and management focuses on a multi-disciplinary team approach to managing individual problems and supporting the patient and family. Echocardiograms and blood pressure monitoring are important to assess for aortic stenosis and hypertension. A low calcium diet may be required to control hypercalcaemia, and they should avoid calcium and vitamin D supplements.