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CSA

Dealing with a Genetics Case

Medical genetics - in VERY basic terms

  • Gene: basic unit of genetic information.
      • It is made up of a DNA.
      • DNA helps makes an RNA product that is either directly functional or makes a protein.
  • Chromosomes – the protein strands around which DNA (and hence genes) is anchored.
      • Each human cell contains 23 pairs of homologous (identical) chromosomes. 
      • So, human somatic cells contain 46 chromosomes, i.e., 46 DNA molecules, of various lengths, which form 23 pairs of homologous chromosomes. 
      • 1 of these 23 pairs is ONE pair of sex chromosome – which consists of either 2 X chromosomes (female genotype) or one X and one Y chromosome (male genotype)  
      • A chromosome pair contains one chromosome inherited from each parent.
  • Germ cells (sperm cells/ova) only contain 23 SINGLE chromosomes (no chromosome pairs!)
      • In other words, they are a haploid chromosome set with only one copy of each chromosome.   (NB every other cell in the body has a diploid set of chromosomes)
      • When a couple have a baby, one part of the pair of each of the 23 chromosomes comes from each parent. 
      • This enables diversity as population generations progress.
  • Expressivity is the extent of expression of a given genotype at the phenotypic level.  In other words, to what extent does the abnormal gene express and manifests itself as a disease?  Patients with Marfan syndrome present with highly variable manifestations of the disease.  Some have mild Marfan’s (arachnodactyly) to a whole variety of presentations including the severe life-threatening (aortic aneurysm) form. 

Know your common genetic disorders & their inheritance

6 types basically listed below.  For the CSA, know the first 3.

Sex linked disorders can also be called GONOSOMAL  disorders  – from the word gonad – referring to the reproductive cells.

X-linked DOMINANT (generally v. v. rare)

    • Alport syndrome
    • Fragile X syndrome
    • Hypophosphatemic rickets
    • Rett syndrome
  • Basic Information
      • The gene responsible for the disease is located on the X chromosome.
      • Both men and women are affected. The second normal X does not protect the female because the condition is DOMINANT.
      • Affected mothers have a 50% risk of passing the altered gene on to their offspring (regardless of gender).
      • Affected fathers will pass the altered gene to all daughters and no sons.  Yes, all sons will be normal.  The sons get a Y from the dad and a healthy X from a healthy unaffected mum.  

X-linked RECESSIVE

    • Becker muscular dystrophy
    • Congenital night blindness
    • Duchenne Muscular Dystrophy
    • G6PD deficiency
    • Haemophilia A & B
    • Lesch-Nyhan syndrome
    • Red-Green colour blindness 
  • Basic Information
      • The gene for the disease is located on the X chromosome.
      • Men, because they only have the one affected X chromosome, always develop the disease!
      • All daughters who inherit the ONE altered X chromosome are carriers
      • Women are usually carriers and, in rare cases, only affected if both X chromosomes are abnormal.
      • Children of a carrier…
          • have a 50% probability of inheriting the altered X chromosome.
          • Sons develop the disease, while daughters are carriers.
          • Frequently skips generations.
      • Carrier female + healthy father = probability that they conceive a phenotypically diseased child is 25%.
      • Healthy female + affected father = all male offspring are healthy, because they inherit a Y from the dad and a healthy X from the mum.   Therefore, they cannot pass on the altered gene because they don’t have it.

Non-sex linked disorders can also be called AUTOSOMAL disorders –    from the word somatic.

Autosomal Dominant

    • Achondroplasia
    • Ehlers-Danlos syndrome
    • Familial hypercholesterolaemia
    • Haemochromatosis
    • HOCM
    • Huntingtons
    • Marfan syndrome
    • Neurofibromatosis (types 1 and 2)
    • Polycystic Disease in Children
    • von Hippel-Lindau disease
  • Basic Information
      • Leads to disease even if only one of the pair of chromosomes is altered.
      • If one parent is affected, every child has a 50% risk of inheriting the disease.
      • Autosomal dominant disorders often vary in their expressivity.

Autosomal Recessive

    • Cystic Fibrosis
    • Haemochomatosis
    • Phenylketonuria
    • Polycystic Disease in Adults
    • Sickle Cell Anaemia
    • Tay Sachs
    • Thalassemias
  • Basic Information
      • The disease occurs only if both pair of chromosomes are altered.
      • Heterozygote (healthy) carriers of a recessive disease are known as carriers and show no phenotypic evidence of the disease.
      • If both parents are heterozygote carriers, the offspring have a 25% probability of inheriting the disease, a 50% probability of becoming a disease carrier, and a 25% probability of being unaffected.  These are numbers worth knowing.
      • Enzyme deficiencies are often inherited in an autosomal recessive fashion.
      • The symptoms of autosomal recessive disorder are usually more severe than those of autosomal dominant disorders and onset of disease is often in childhood .
      • Increased risk in families with consanguinity
  1. Downs Syndrome – trisomy on chromosome 21 – presence of all or part of a third copy of chromosome 21.
  2. Polysomy – Klinefelters  (47XXY)  – extra X sex chromosome in males, XYY syndrome, Triple X syndrome (XXX)
  3. Monosomy – Turners  (45X0 or 45X)  – missing an X in the sex chromosome pair in females.
  • Basic Information
    • Numerical chromosomal aberrations: an abnormal number of copies of a single chromosome –  extra or missing chromosome
    • Remember, normal humans have a pair of 23 chromosomes i.e. 46 chromosomes in total in every somatic cell.
  • Leber hereditary optic neuropathy
  • Mitochondrial Myopathies (e.g. MELAS syndrome)

Basic information

  • Mitochondrial DNA is maternally inherited.
  • Diseases caused by mutations in mitochondrial DNA are only passed down from mother to offspring.
  • Any offspring of an affected mother may show signs of the disease.
  • Heteroplasmy:  Each mitochondrion has multiple copies of DNA (mtDNA), and each cell has many mitochondria. All of the DNA within the mitochondria is the same. If a mutation occurs, it usually is observed only in some of the mtDNA copies. This heterogeneity among mutated and normal mtDNA is known as heteroplasmy.
  • Disease severity often correlates with the proportion of mutated mtDNA copies.

Hopefully, mitochondrial abnormalities will not come up in the CSA exam.  It’s confusing enough with the other genetic abnormalities.  We are training to be GPs, not geneticists!

  • Androgenic Alopecia
  • Alzheimer’s disease
  • Atopy
  • Diabetes Mellitus (Types 1 & 2)
  • Hypertension
  • Schizophrenia

Basic Information

  • Polygenic diseases are the result of an interaction of two or more genes.
  • Polygenic diseases do not follow Mendelian laws of inheritance.
  • It’s not just genetic diseases that are a result of an interaction of two or more genes.    Other (normal) things are too like eye colour, skin colour, height and weight.
  • These are disorders that are influenced by various factors (genetics, external influences like lifestyle and environment)
  • Most diseases are caused by multiple factors
  • Many people think most cancers are inherited disorders – they are not.
  • Most cancers are a result of various factors – where lifestyle and environment plays a major part on the genetics eg smoking.

In the CSA, if you get anything else, the case will tell you more about the genetic disorder (i.e. whether it is autosomal recessive or dominant for instance).   So, do not be phased or get anxious about a condition you have not heard of.  The station will probably be designed that way – i.e for most GP trainees NOT to know and they’re wanting to see how you handle it.in 

Know your numbers or be able to do a Punnet diagram

Sex-linked
 

Parents

Possible Children

If X-linked DOMINANT (XD)

If X-linked RECESSIVE (XR)

XFY   +   XX

XD & XR:

dad affected – mum ok

XFX, XFX, XY, XY

·       All females affected

·       All males normal

·       All females carriers

·       All males normal

XFY   +   XFX

XD: dad affected – mum carrier

XR: dad affected – mum affected

XFXF, XFX, XFY, XY

·       All females affected

·       Half males affected 

·       Half males normal

 

·       Half females affected

·       Half of females carriers

·       Half of males affected 

·     Half of males normal

XFY   +   XFXF

 

XD & XR:

dad affected – mum affected

XFXF, XFXF, XFY, XFY

·       All females affected

·       All males affected

·       All females affected

·       All males affected

XY   +   XFX

common scenario

XD: dad ok – mum carrier

XR: dad ok – mum affected

XXF, XX, XFY, XY

·       Half females affected

·       Half females normal

·       Half males affected

·       Half males normal

·       Half females carriers

·       Half females normal

·       Half males affected

·       Half males normal

XY   +   XFXF

 

XD & XR:

dad ok – mum affected

XXF, XXF, XFY, XFY

·       All females affected

·       All males affected

·       All females carriers

·       All males affected

 
  • F = faulty chromosome
  • Remember, in Dominant condition, a female need both X’s to be affected i.e. XFXF.   But in men, because they only have one X and not another one to protect them, XFY = an affected male (not a carrier).
  • So, consider the female (XX) with ONE faulty X gene – she is affected if Autosomal Dominant, but a carrier if Autosomal Recessive (the other normal X compensates).
  • Consider the male (XY) with a faulty X gene – he is affected if Autosomal Dominant, BUT he is also affected if Autosomal Recessive because men do not have another X to compensate like in females.
  • How to explain one of these rows to a patient?  Let’s pick X-linked ROW 2: “There is a 50:50 chance of you having a boy or a girl.  If it is a boy, then there is a 50% chance they can be affected and a 50% chance they will be normal.  However, if you have a girl, unfortunately all girls will be affected.”
Non-sex Linked

 

Parents

Possible Children

If Autosomal DOMINANT (AD) 

If Autosomal RECESSIVE  (AR)

HH   +   HF

 

AD: one parent ok, other affected

AR: one parent ok, other carrier

HH, HF, HH, HF

1 in 2 normal

1 in 2 affected

(50% healthy, 50% affected)

1 in 2 normal

1 in 2 carriers

(50% healthy, 50% carriers)

HH   +   FF

 

AD & AR:

one parent ok, other affected

HF, HF, HF, HF

All affected

No normal

All carriers

No normal

HF   +   HF

 

AD: both parents affected

AR: both parents carriers

HH, HF, HF, FF

1 in 4 normal

3 in 4 are affected

1 in 4 normal

2 in 4 carriers

1 in 4 affected

HF   +   FF

 

AD: both parents affected

AR: one parent carrier, other affected

HF,  HF, FF, FF

All are affected

No normal

1 in 2 carriers

1 in 2 affected

No normal

FF   +    FF

 

AD & AR:

both parents affected

FF, FF, FF, FF

All affected

No normal

All affected

No normal

Notes

  • H = Healthy chromosome.   F = faulty chromosome
  • In dominant condition, you only need one faulty gene to be present.  In a recessive condition, you need two – because on it’s own one is not strong enough – if only the one is present, the person is a carrier.  Hence there are no carriers in a dominant condition.
  • So, a person who has one normal gene and one faulty gene is AFFECTED as an individual if the condition is Autosomal Dominant.  However, they are a carrier if the condition is Autosomal Recessive (because the other normal chromosome compensates).  It does not matter if they are male or female, because the gene abnormality is NOT on the sex chromosome but on one of the other 22 chromosomes instead.  (remember, we have 23 PAIRS of chromosomes, of which ONE is the sex chromosomes, leaving 22 others.
  • In Autosomal Recessive: if both parents are heterozygote carriers (HF + HF), the offspring have a 25% probability of inheriting the disease, a 50% probability of becoming a disease carrier, and a 25% probability of being unaffected.  These are numbers worth knowing.
  • Remember, in Cystic Fibrosis, 1 in 25 of the general population are a carrier of the disease and don’t know it.  This is called the Heterozygote frequency.  So, if someone says “I think my partner’s side is okay, I don’t recall any lung problems” tell them “Okay, but it is important to get your partner tested because we know that it is a common gene fault and many people don’t even know they have it!”.   
  • Did you know that the incidence of CF is 1 in 2500.   1 in 25 is the heterozygote frequency – i.e. 1 in 25 people have one of their chromosomes affected.  Don’t you think that’s quite a large frequency?  

Know your terms and how to explain them

  • Chromosomes, Genes and DNA =  refer to as packets of information or information map.  You don’t have to explain any more detail to patients – it will just bore them.    Patients generally don’t need to know the differences between chromosomes, genes and DNA like the way we do.  So instead, refer to all of them as “packets of information that usually come in pairs – one of the pair from each of our parents”.
  • “Have you heard of the word genes before? So, genes are basically packets of information that tell your body how to make every part of you – they are they reason why everyone is so unique.   Everyone has two packets.  So, you’ve got two packets and one of those packets came from your mum and one from your dad.  Likewise, when you go on to have children, your child will have two packets of information, one from you and one from your partner.  Does that make sense so far.”
  • Carrier = “a carrier is a person who carries a faulty gene but does not have the condition because you usually need two sets of the faulty gene, not just the one.  The problem is that whilst they don’t physically have that condition, they can pass that faulty gene on.  And so, if that person marries another person with also a faulty gene – they can both then produce kids who have two lots of faulty genes (one from each parent) meaning the newborn ends up with the genetic condition”.  Remember, it applies to recessive conditions usually. 

Data Gathering Tips

  • When working out risk, one of the important things to do is to check that the person asking is not adopted or whether aunts and uncles affected (etc) are adopted or whether genetically confirmed uncles and aunts.  
    “You said your cousin sister is affected.  Can I check that her mum, your aunt, is your mum’s genetic sister and not an adopted sister”

Explanation Tips

    • When explaining risk, explain things in terms of absolute numbers is generally better than percentages.  It’s a lot easier to understand.
        • For example, people understand 1 in 4 chance better than 25%.   
        • One exception to the rule in 1 in 2 – which most people understand 50:50 or a 50% chance probably better.  
        • 0% and 100% are also more easier to understand that  0 in 4 chance or 4 in 4 chance respectively.  However, unless you absolutely and categorically know that both parents have normal genotypes, you cannot usually say zero percent or one-hundred percent.
    • Also remember that the risk of a genetic condition RESTARTS with every new baby.
        • Explain that this is risk – or “the chance of you having…” – and that chance resets itself with each newborn.   Just because you have had three children that are normal, does NOT mean the next is more likely to be abnormal.   It is the same risk as for the previous children.
            • Patient says: “Doctor, I’ve got one child who is fine.   Does that mean the next one has a higher chance of being affected”.  
            • Doctor should say “Absolutely not.The risk restarts with every new baby.  So, the chance of your baby having the condition is still 1 in 4”.
        • OR
            • Patient says: “So doctor, you said that there is a 1 in 2 chance of my future children being carriers.  I’ve already had one normal one.  Does that mean my next one is going to be a carrier?” 
            • Doctor’s reply: “No, it doesn’t work like that.  What I am talking to you is about the risk of being a carrier.    That risk restarts with every newborn – so the chance is still 50:50 and that risk is unaffected by whether previous children are affected or not.
  • You don’t always need to draw genetic combination diagrams and explain that to the patient.
        • If you know your figures, you can just say your figures.   Everyone automatically thinks the way to explain inheritance to a patient is to draw sort of Punnet tables or diagrams – but patients really come in for the figures, not the working out!  They are interested in “the risk of my child having xxx” end of.   
        • But if you don’t know your figures, then you can draw your genetic combination diagram and you may wish to share this with the patient.   If you are doing this, then see the videos on how to do it.   Slow down when exlplaining.  Remember, most patients are not mathematicians.  And most don’t understand Mendelian genetics like you do (even if it seems basic to you).

Videos in action

  • DOCTOR LETS PATIENT SPEAK, LISTENS, EMPATHISES, CLARIFIES TO CREATE RAPPORT AND BUILD TRUST.
  • DOCTOR EXPLAINS HOW INHERITANCE GENERALLY WORKS IN HUMANS
  • The maths in this video are wrong.  Stop watch at 47 seconds.
  • DOCTOR EXPLAINS USING MENDELIAN GENETICS
  • The maths in this video are wrong for sex-linked recessive disorders.  Men cannot be carriers.
  • This is the perfect explanation though for a non-sex linked Autosomal Recessive Disorder.
  • This video is being show for the way the doctor expertly explains things in a simple manner, using a diagram and her fingers to point things out.   
  • It is NOT being shown for the accuracy of the mathematics.
  • DOCTOR EXPLAINS BRIEFLY TOUCHING ON MENDELIAN GENETICS
  • The maths in this video are wrong for sex-linked recessive disorders.  Men cannot be carriers.
  • This is the perfect explanation though for a non-sex linked Autosomal Recessive Disorder.
  • This video is being show for the way the doctor expertly explains things in a simple manner, using a diagram and her fingers to point things out.   
  • It is NOT being shown for the accuracy of the mathematics.
  • DOCTOR EXPLAINS USING NO MENDELIAN GENETICS EXPLANATION
  • The maths in this video are wrong for sex-linked recessive disorders.  Men cannot be carriers.
  • This is the perfect explanation though for a non-sex linked Autosomal Recessive Disorder.
  • This video is being show for the way the doctor expertly explains things in a simple manner, using a diagram and her fingers to point things out.   
  • It is NOT being shown for the accuracy of the mathematics.

We will re-do these videos when time allows. 

  • One for sex link disorders
  • One for autosomal recessive disorders

Please leave a comment if you have a tip, spot an error, spot something missing or have a suggestion for a web resource.
And of course, if you have developed a resource of your own, please email it to me to share with others.

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