Patterns of Disease Inheritance
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Mendelian inheritance is a term sometimes used to describe patterns of inheritance, based on the original ideas of dominant and recessive genes, first proposed by the Gregorian Monk Mendel.
Determining patterns of inheritance is greatly aided by the use of pedigrees. Drawing out the ‘family tree’ and highlight affected individuals is a good way of noting down a lot of information without having to write much, and also makes the pattern easier to spot.

Autosomal Dominant Inheritance

(aka vertical transmission) – thousands of conditions
  • ‘Autosomal’ – refers to the fact that the affected gene is present on an autosome (chromosomes 1-22) rather than on a sex chromosome.
  • The most common type of mendelian inheritance
  • Humans carry two copies of a gene – one from the mother, and one from the father. This is known as heterozygousity.
  • In autosomal dominant inheritance, the affected individual will have one ‘good’ copy of the gene, and one ‘bad’ copy. They are heterozygous for the affected gene.
    • This is contrary to autosomal recessive conditions, where to be affected, an individual has to be homozygous for a particular gene (they have to have two ‘bad copies’).
  • Only one ‘bad’ copy is required for phenotypic features
  • There is no carrier state – if you carry an affected gene, then you will have an affected phenotype
  • Punnett’s square is an easy way to determine the risk of an affected individual passing on the risk to their child.
    • The affected gene is noted by a capital letter (in this case ‘A’). The unaffected gene is noted by the same lower case character (a).
  • An affected parent typically has a 50% chance of passing on the defect to any of their offspring.
  • Typically, the genes involved affect the production of structural proteins.

Concepts in Autosomal Dominant Inheritance

  • Pleiotropy – this is the ability of an affected gene to cause two or more seemingly unrelated clinical effects.
    • in some cases, an autosomal dominant gene may only have one obvious clinical effect (e.g. congenital cataracts)
    • More commonly, a single gene defect has severl clinical effects. This is pleiotropy.
  • Variable Expressability – even within the same family, an inherited genetic defect can cause massively different degrees of clinical effect. From mild to severe symptoms.
  • Reduced penetrance – this is the phenomenon whereby an individual in the family may carry the autosomal dominant gene but may not show any clinical features. The clinical features have ‘skipped a generation’.
    • Somebody who is heterozygous for a defective gene but has no clinical features is said to be reperesent non-penetrance.
    • Most conditions are around 80% penetrant. Very few are 100%. One particular example of 100% penetrance is Huntington’s disease.
  • Knowing the above phenomenon is important when looking at pedigree’s. For example, don’t let an instance of non-penetrance confuse you into thinking it is not autosomal dominant!
  • New mutations can occur where there is no family history. in some cases, these may e autosomal dominant mutations that can subsequently be passed onto offspring.
    • New dominant mutations have been associated to advancing paternal age.
  • Homozygousity in autosomal dominant traits
    • Although rare this is possible. It usually results when the affected individual had parents who were both heterozygous.
    • Symptoms are typically worse than the heterozygous state
  • Codominance – this is where two dominant states are expressed simultaneously in the same individual. A simple example is an individual of AB blood type, who expressed both group A and group B proteins.
  • Gonadal mosaicism –only a small proportional of gonadal cells are affected. Thus the parent has no clinical signs, but may pass on the defect to children.
An Apparent case of an autosomal dominant condition – but parent’s aren’t affected? – don’t forget that the apparent father may not be the actual father!

Example diseases

Autosomal Recessive Inheritance

Hundreds of conditions
  • Affected cases occur when both parents are carriers of a particular mutation.
  • To be affected, you must have two copies of the affected gene.
  • The risk of having an affected child when both parents are carriers is 25%, and the chance of having a child who is a carrier is 50%.
    • If one parent is homozygous, and one is only a carrier, then they have a 50% chance of having an effected child. In this situation, this phenomenon is sometimes called pseudodominance.
  • It is thought that almost everyone in the population will carry a recessive gene for one condition or more – but usually we have children with partners who carry a different recessive gene. 
  • Consanguinity  (parents are related; Generally the risk is higher the more closely the parents are related) increases the risk of having an affected child – as it increases the risk that both parents carry an affected gene.
    • The risk for the general population is roughly 2%
    • The risk for a consanguineous couple is roughly 4%
  •  Typically the genes involved affect metabolic pathways
Autosomal Recessive Inheritance
Autosomal Recessive Inheritance. Image: U.S. National Library of Medicine
Phenomenon in autosomal recessive inheritance
  • Locus heterogeneity – this refers to the phenomenon whereby there may be more than one recessive gene that accounts for a particular condition. For example, sensorineural hearing loss. In such cases, often two deaf individuals will have children together, you would expect that this would mean they had a 100% chance of having an affected child, but many children are born with normal hearing. This is because the affected parents have different mutations at different loci – and thus the mutations can be treated as separate, and thus it is as if only one parent is affected.
    • A disorder where the same phenotype can result from different mutations is known as a genocopy.
  • Mutational heterogeneity – this is the phenomenon whereby there are different mutations, but at the same loci. In reality, the vast majority of autosomal recessive cases will be due to mutational heterogeneity, and perhaps a small proportion will be truly homogeneic, particularly in consanguineous couples.

Example diseases

  • Sickle cell disease – 1 in 625 (Black Africans)
  • Cystic fibrosis 1 in 2500 (Caucasians)
  • Tay-Sacs disease – 1 in 3000 (Jews)

Sex Linked Inheritance

A few hundred conditions
X-linked Recessive – aka Knight’s move or diagonal inheritance
  • Accounts for the vast majority of sex linked cases
  • Only males are usually affected
    • Females are usually only carriers (but sometimes females may show mild clinical signs – manifesting carrier)
  • Sons of female carriers have a 50% risk of being affected
    • And likewise, each daughter of a female carrier has a 50% chance of being a carrier
  • Daughters of affected males will all be carriers
    • SONS OF AFFECTED MALES ARE NOT AFFECTED! – because men pass on the Y chromosome to their sons
  • X-linked disorders are often clinically severe
    • Often the family history is weak (there is often gonadal mosaicism, and few affected relatives). Drawing out a good pedigree may be necessary to identify those at risk
    • Despite a weak family history, genetic testing and counselling can be necessary, as all carrier females have a 50% risk of having an affected son, whoever their partner is.
    • Sometimes called ‘Knight’s move’ inheritance – as it apparently skips generations, and presents with unusual pedigree patterns.
  • An affected male is said to be ‘hemizygous’ for the mutation


  • Red-Green colour-blindness
  • Duchenne’s and Becker’s Muscular Dystrophies
  • Fragile X syndrome
  • Glucose-6-phosphate dehydrogenase defriciency
  • Haemophilia A and B
  • Hunter’s Syndrome

X-linked Dominant

These conditions are rare compared to their recessive counterparts.
  • Both men and women will show equal phenotypes.
  • Often presents like an autosomal dominant trait – but there is an important difference: For affected females:
    • 50% chance of passing on the gene
    • Sons and daughters at equal risk
  • Unlike autosomal dominant – for affected males
    • All daughters will be affected
    • No sons will be affected
  • An example of a condition is vitamin D resistant Rickets.

Y-linked inheritance

Such conditions are extremely rare. They only affect males, and an affected man will pass on the gene to all his sons. The Y chromosome is typically only associated with spermatogenesis, and thus any conditions involving Y-linked inheritance will typically result in infertility.

Mitochondrial / Cytoplasmic Inheritance

Mitchondria have their own DNA. Each cell has 1,000 copies of mitochondrial DNA, but typically, only a proportion of the mitochondrial DNA is affected.
  • Mitochondrial DNA is only passed on through the mother – only the oocyte contain mitochondrial DNA and not the sperm. Thus fathers with mitochondrial DNA disorders will not pass the defect onto their children.


For some genes, the copy received from one parent has different activity to the copy received from the other parent. This phenomenon is known as imprinting, and is normal. However, it does mean that when one copy is abnormal, it can result in genetic defects. For example: Prader-Willi syndrome
  • Clinical features – learning difficulties, hypotonia, obesity. A particular problem is that the affected children eat anything and everything! One patient was known to eat their whole carpet.
  • In this condition, there is a defective gene copy received from the father. The copy received from the mother is not used, even if it is ‘normal’ copy.
  • Thus the child must inherit the active gene from the father inorder to be free of the disease. If for any reason, no paternal copy is received, then the syndrome will result. Failure to receive the gene can be due to a de novo deletion, or it can be the result of Uniparental disomy – where two copies of one gene are received from the same parent.

Polygenic / Mul​tifactorial Inheritance

There are many disorders for which there are many environmental and genetic factors at play that account for an individual’s overall risk of contracting the disease.
In such conditions, the exact genetic makeup is usually complex, and cannot be accounted for by a specific gene, however, there will often be a family history of the condition(s) to which the child is more susceptible.
Genes that make you susceptible to a condition increase your risk of contracting the condition, but don’t necessarily mean you will get it.
The risk is particularly increased when:
  • You have a close relative with the disorder
  • Several members of the family have the disorder
  • The disease is known to be sex specific, and you are of that particular gender
  • A relative has had a particularly severe form of the disease
A good way of illustrating how the risk of a condition increases with this kind of polygenic risk is with a normal distribution:

Some common conditions known to be multifactorial include:

Congenital Disorders:

  • Neural Tube Defects
    • + environmental factors (folate)
  • Congenital Heart Disease
  • Cleft lip and palate
  • Pyloric Stenosis
  • Congenital dislocation of the hip
  • Talipes
  • Hypospadias

Other Conditions:

In many of the disorders the possible environmental factors are not fully understood


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Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

This Post Has 2 Comments

  1. Andreas Rossberg

    Your autosomal recessive punnett square is wrong – the homozygous recessive possibility is affected – not the homozygous dominant!

  2. Dr Tom Leach

    Hi Andreas, thanks for this, I have fixed it up! Tom

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