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Genes & Inheritance

Posted By Paul Gardener, June 9, 2013

On this page we look at the inheritance of JHS, EDS, Marfan syndrome and Stickler syndrome.

1. Joint Hypermobility Syndrome (JHS) or Ehlers Danlos Hypermobility Type (EDS-HM)?

Is there a genetic test for JHS / EDS-HM?

The short answer is, No.

For the vast majority of individuals there is no genetic test to assist in making a diagnosis. The diagnosis is a clinical one. Even in some individuals and families considered to have the Classical or Vascular forms of EDS or Marfan Syndrome for example where there are genetic tests, the results of these tests may not be clear cut and can be difficult to interpret.

Geneticists are currently working on gene tests by looking at the genes of whole families (often 3-4 generations) of people with JHS / EDS-HM.

There have been studies showing that in a small portion of people with EDS-HM the low expression of a gene that controls the production of structural protein called Tenascin X has been found. However, this only seems to arise in less than 10% of families and currently this is not a routine or diagnostic test in use.

What is the inheritance of JHS / EDS-HM?

First, we know that hypermobility in itself is strongly inherited. This is called a ‘dominant’ pattern of inheritance. However, the pattern of the hypermobility (the joints involved, and the degree to which they are hypermobile) is very variable in different members of the same family.

We also know from studying families that the more complex issues that lead to the diagnosis of JHS / EDS-HM have a dominant pattern of inheritance. However, like hypermobility, the patterns of presentation can be very different. The types of problems and the severity of these vary within the family. Indeed some family members may have minimal problems so mild that they do not seek medical advice as it is just not needed.

Why one person with hypermobility or one member of a family with hypermobility should develop a variety of complications and another person with hypermobility be absolutely well is simply not understood.

What are the chances of a child getting problems if mum or dad has JHS or EDS?

Although the hypermobility is strongly inherited this may be of no medical consequence at all. Also, children, and in particular infants and toddlers, are naturally hypermobile in many cases. The hypermobility may or may not lessen as the child grows.

Perhaps the most practical thing to do is to be alert to the fact that the child is hypermobile and if they seem to be developing problems (for example: delay in their ‘developmental milestones’ (crawling, walking), clumsy, joint pains, perhaps poor hand-writing skills at school, bruising or scarring easily) then ask a doctor whether the presence of the hypermobility might be related to or causing the problem.

To read more about Dominant and Recessive Genes and Inheritance of EDS take a look HERE.

2. Genes we know about in EDS, Marfan syndrome and Stickler syndrome

Autosomal_dominant_-_en

 

EDS

The Villefranche nosology (currently being revised) for EDS recognizes six subtypes of the condition based on the nature and severity of the clinical features, the underlying biochemical and genetic defect, and the pattern of inheritance. Mutations in genes encoding collagens (COL) I, III and V, and collagen-modifying enzymes have been identified in most forms of EDS. EDS Classical type is a dominant disorder caused by mutations in COL5. Mutations of COL1 are associated with the very rare variant EDS Kyphoscoliotic type, and those of COL3 with EDS Vascular type. Take a look at Criteria for EDS, a page in Help and Advice on this website.

Image from Wikipedia – http://en.wikipedia.org/wiki/Dominance

 

Marfan syndrome

The Marfan syndrome has a dominant inheritance and is associated with mutation of fibrillin 1 and 2. To read more about the criteria for diagnosing Marfan Syndrome click HERE, but please note this takes you to the National Marfan Foundation, a organisation based in the USA.

Stickler syndrome

There four genetic changes known in Stickler syndrome. The first, an alteration of COL2 is responsible for about 3/4 of all cases and is dominantly inherited. Two different types of COL11 gene abnormalities exist also, and there is a 4th more rare and recessive inherited COL9 variant. To read more about Sticklers see the HMSA Journal Spring 2015.

3. Dominant vs Recessive Genes

For every characteristic we have (e.g., our hair colour, eye colour etc) we have two copies of the gene. One of this pair may be stronger than the other i.e. ‘Dominant’, and the proteins/molecules/structures it codes for over-ride others produced by the other gene in the pair. This dominance is then seen through the generations. If one parent has 1 dominant gene for a condition and the other parent has none then there is a 50:50 chance of an offspring inheriting the gene and expressing the condition. If both parents have 1 dominant gene there is a 75% chance of an offspring inheriting the gene (and a 25% chance that the offspring will inherit the dominant gene from both parents). If someone has 2 dominant genes (i.e. both genes in the pair) then there is a 100% chance of passing this on to the next generation.

Some genes are described as ‘Recessive’. Their effect, i.e. proteins / structures etc may not have any effect / influence if there is a stronger effect from the dominant paired gene. For a recessive disorder to be expressed clinically in an offspring both copies of the gene (one from each parent) need to be recessive. Often parents will be ‘carriers’ – they have one copy of the gene that is recessive but suppressed by the other, and therefore do not show any clinical signs. However, when each parent then passes on their copy of the recessive gene to a child, the child has 2 recessive genes and so the gene and the condition or characteristic is expressed.

There is an opposite effect: one parent may have 2 recessive genes, but the other parent have no recessive genes. The second parents’ genes will dominate and as such offspring are ‘carriers’ and may not show any of the recessive condition or characteristics; the condition seems to ‘skip’ a generation.

4. How are the gene tests done?

This is by blood test and can be arranged through several national specialist centres.

 

Dr Alan J Hakim MA FRCP
Consultant Physician and Rheumatologist
Hon. Senior Lecturer
Barts Health NHS Trust and Queen Mary University London

Written June 2013. Updated February 2015. Planned Date of Review June 2016

Academic Reference

Annunen S, Korkko J, Czarny M et al. Splicing mutations of 54-bp exons in the COL11A1 gene. Am J Hum Genet 1999; 65(4):974-83.

Liberfarb RM, Levy HP, Rose PS et al. The Stickler syndrome: genotype/phenotype correlation in 10 families with Stickler syndrome resulting from seven mutations in the type II collagen gene locus COL2A1. Genet Med. 2003; 5(1):21-7.

Pope FM, Burrows NP. Ehlers Danlos syndrome has varied molecular mechanisms. J Med Genet 1997; 34: 400-10

Malfait F, Hakim AJ, De Paepe A, Grahame R. The genetics of Joint Hypermobility Syndrome. Rheumatology 2006, 45: 502-7


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