Identification of genes and mutations in genetic skeletal diseases leads to improved diagnosis and counselling through an international clinical and DNA diagnostic network
Submitting InstitutionUniversity of Manchester
Unit of AssessmentBiological Sciences
Summary Impact TypeHealth
Research Subject Area(s)
Biological Sciences: Biochemistry and Cell Biology, Genetics
Medical and Health Sciences: Neurosciences
Summary of the impact
Genetic skeletal diseases (GSDs) are an extremely diverse and complex
group of genetic diseases that affect the development of the skeleton.
Although individually rare, as a group of related genetic diseases they
have an overall prevalence of at least 1 per 4,000 children, which
extrapolates to a minimum of 225,000 people in the European Union. This
burden in pain and disability leads to poor quality of life and high
healthcare costs. GSDs are difficult diseases to diagnose and there are
currently no treatments, therefore, arriving at a confirmed diagnosis is
vital for clinical management, psycho-social support and genetic
Research conducted at the University of Manchester (UoM) has had a major
influence on establishing the correct diagnosis of specific GSDs by the
discovery of causative genes and mutations and the subsequent development
of accurate and reliable DNA testing protocols. This has significantly
improved both accuracy of, and access to, genetic testing in the UK,
Europe and worldwide.
This impact case is the direct result of research that took place at UoM
from 1996 to 2012. The key researchers were:
Dr Michael Briggs (Senior Research Fellow, 1996-2012)
Dr Kathryn Chapman (Post-Doctoral Research Associate, 1999-2001)
Dr Paul Holden (Research Associate / Post-Doctoral Research Associate,
Dr Gail Jackson (Post-Doctoral Research Associate, 2002-2010)
The aim of the original research programme was the identification and
characterisation of the genes and mutations responsible for a diverse
range of GSDs, including pseudoachondroplasia (PSACH), multiple epiphyseal
dysplasias (MED) and various spondylo-epi-metaphyseal dysplasias. This
information was subsequently used to establish DNA diagnostic protocols
and a pan- European diagnostic network for GSDs (2002 to date). The key
discoveries were as follows:
- Discovery that mutations in the gene encoding matrilin-3 (MATN3)
cause a form of autosomal dominant MED (EDM5)  with the subsequent
identification of a definitive range of disease causing mutations .
- Confirmation that mutations in the genes encoding type IX collagen 
and cartilage oligomeric matrix protein (COMP)  result in a wide
range of phenotypes within the PSACH-MED disease spectrum.
- The identification and characterisation of this definitive range of
disease causing mutations in these genes allowed development of accurate
molecular diagnosis protocols that also have pre- symptomatic and
pre-natal applications [4-6].
A DNA diagnostic service for PSACH-MED phenotypes was developed and
subsequently improved [4-6]. The concurrent establishment of a
trans-national diagnostic network has improved diagnosis and mutation
detection rates for these diseases. The on-line case management system
allows clinicians to submit cases directly to the European Skeletal
Dysplasia Network (ESDN) from anywhere in the world, thereby expediting
access to expert advice.
References to the research
The research produced a complementary series of publications, many of
which are in high impact journals and/or leading journals in the field
(ISI Journal Rankings 2010 - Genetics and Heredity).
1. Chapman K.L., Mortier G.R., Chapman K., Loughlin J.A., Grant
M.E., Briggs M.D. (2001) Mutations in the region encoding the von
Willebrand factor A domain of matrilin-3 are associated with multiple
epiphyseal dysplasia. Nat Genet. 28 (4). p. 393-396. DOI:
2. Jackson G.C., Barker F.S., Jakkula E., Czarny-Ratajczak M.,
Makitie O., Cole W.G., Wright M.J., Smithson S.F., Suri M., Rogala P.,
Mortier G.R., Baldock C., Wallace A., Elles R., Ala- Kokko L., Briggs
M.D. (2004) Missense mutations in the beta strands of the single
A-domain of matrilin-3 result in multiple epiphyseal dysplasia. J Med
Genet. 41 (1). p. 52-59. DOI:10.1136/jmg.2003.011429
3. Holden P., Canty E.G., Mortier G.R., Zabel B., Spranger J.,
Carr A., Grant M.E., Loughlin J.A., Briggs M.D. (1999)
Identification of novel pro-alpha2(IX) collagen gene mutations in two
families with distinctive oligo-epiphyseal forms of multiple epiphyseal
dysplasia. Am J Hum Genet. 65 (1). p.31-38. DOI: 10.1086/302440
4. Kennedy J., Jackson G.C., Ramsden S., Taylor J., Newman W.,
Wright M.J., Donnai D., Elles R., Briggs M.D. (2005) COMP mutation
screening as an aid for the clinical diagnosis and counselling of patients
with a suspected diagnosis of pseudoachondroplasia or multiple epiphyseal
dysplasia. Eur J Hum Genet. 13 (5). p.547-555. DOI:
5. Zankl A., Jackson G.C., Crettol L.M., Taylor J., Elles R.,
Mortier G.R., Spranger J., Zabel B., Unger S., Merrer M.L., Cormier-Daire
V., Hall C.M., Wright M.J., Bonafe L., Superti-Furga A., Briggs M.D.
(2007) Preselection of cases through expert clinical and radiological
review significantly increases mutation detection rate in multiple
epiphyseal dysplasia. Eur J Hum Genet. 15 (2). p. 150-154. DOI:
6. Jackson G.C., Mittaz-Crettol L., Taylor J.A., Mortier G.R.,
Spranger J., Zabel B., Le Merrer M., Cormier-Daire V, Hall C.M., Offiah
A., Wright M.J., Savarirayan R., Nishimura G., Ramsden S.C., Elles R.,
Bonafe L., Superti-Furga A., Unger S., Zankl A., Briggs M.D.
(2012) Pseudoachondroplasia and multiple epiphyseal dysplasia; a 7-year
comprehensive analysis of the known disease genes identify novel and
recurrent mutations and provides an accurate assessment of their relative
contribution. Hum Mutat. 33 (1). p.144-157. DOI:
Details of the impact
GSDs are an extremely diverse and complex group of rare genetic diseases,
for which diagnosis can be difficult for the non-expert. There are more
than 450 unique and well-characterised phenotypes that range in severity
from relatively mild to severe and terminal forms. The accurate diagnosis
of a specific GSD therefore usually necessitates several types of
investigation such as review of the child's medical and family history,
physical examination, genetic testing and radiological evaluation.
Moreover, genetic mutational analysis plays a pivotal role in establishing
the correct diagnosis and in facilitating clinical management, accurate
risk assessment and genetic counselling for family members. Before Brigg's
discoveries, the diagnosis of some GSDs (i.e. PSACH-MED-SEMD) relied
entirely upon clinical and radiological methods. Brigg's research
introduced a completely new paradigm in rare disease diagnosis by
demonstrating that a trans- national clinical and molecular diagnosis
network (ESDN) could dramatically improve patient access to expert
diagnosis for GSDs and also increase mutation detection rates.
Pathways to impact
Development of gene specific DNA tests for PSACH-MED
The identification of causative genes and mutations for PSACH-MED, namely
COMP, MATN3 and the type IX collagen genes (COL9A1-3),
allowed the development of gene specific DNA diagnostic tests. These tests
were originally offered to 5-10 clinicians on a `research basis' by the
Briggs laboratory, however, the un-sustainability of this approach in a
non-accredited laboratory, led to the inclusion of these diagnostic tests
in the portfolio of the Regional Molecular Genetics Laboratory at St
Mary's Hospital in Manchester. Initial funding for this service was
provided by the PPP Healthcare Trust (2001-2003) and then subsequently
through the European Commission 5th and 6th
Framework Programmes (2002-2010). The success of the PSACH-MED diagnostic
service allowed a sustainable financial model to be applied in early 2010
and the referring clinicians now pay for all testing via the NHS or health
insurance (overseas referrals).
Establishment of the first trans-national diagnostic network for
The European Skeletal Dysplasia Network (ESDN) was first established in
January 2002 with a grant from the European Commission with a remit to
develop an integrated research and diagnostic network for skeletal
dysplasias. This was the first trans-national diagnostic network
for any genetic disease grouping.
Reach and significance of the impact
Development of gene specific DNA tests for PSACH and MED
Specific DNA tests that allow earlier and more accurate diagnosis (also
prenatal and predictive testing) are now available to UK families through
the Regional Genetic Laboratory (Manchester) [A] and these protocols have
also been widely adopted in other testing laboratories across Europe [B],
North America [C] and elsewhere. Indeed, there are now 19 diagnostic
centres in Europe [B], three in North America and one centre in Korea [C]
offering DNA testing for PSACH-MED. In most of these centres, the current
service is still based on Brigg's screening protocols and molecular
diagnosis has been provided to 100s of patients with PSACH, MED and
related diseases. For example, representative sampling of COMP diagnostic
testing performed by three referral laboratories located in different
geographical areas has revealed the following number of tests were
A similar number of tests were also performed for MATN3 and the
type IX collagen genes. These numbers do not include the testing of
additional family members for prenatal and predictive purposes, which
plays a major role in providing counselling and reproductive options to
From this 5-year sampling it is clear that there was a consistent number
of tests performed each year and that the adoption of a charging policy in
Manchester at the beginning of 2010 did not drastically reduce the numbers
of referrals, thereby demonstrating the clinical requirement and utility
of these tests. In summary, the availability of these reliable and rapid
genetic tests has had a major impact on the delivery of genetic healthcare
to patients worldwide.
Undiagnosis or misdiagnosis causes considerable psychosocial problems.
Having the correct genetic diagnosis aids prenatal testing and guides in
predictive and prognostic aspects.
Establishment of the first trans-national diagnostic network for
The European Skeletal Dysplasia Network (ESDN) was one of the first
networks of expertise in the field of rare diseases to use information and
communications technology (ICT) tools for the purposes of tele-expertise
and medical diagnosis [G]. From September 2003, ESDN has received over
1600 referrals through the on-line Case Manager and 450 users have
accessed the ESDN Case Manager from 45 different countries worldwide. For
example, the following referrals were made in the period 2008-2012
|Number of referrals
Referrals in 2008-2012 have come from regional genetics centres in 20 UK
cities (240 patients), 23 different European countries (469 patients) and
13 countries outside of Europe (223 patients) including [H]:
|Number of referrals
Interestingly, the period 2008-2011 has seen a significant increase in
referrals from emerging economies. For example, ESDN received 8 referrals
from India between 2003-2007 and this has increased dramatically to 108
during the 4-year period 2008-2012 [H], confirming that ESDN is providing
a solution to an unmet medical need in these countries.
Overall, these data confirm the international reach and impact of ESDN
and demonstrate how this network approach has transformed the diagnosis of
genetic bone diseases worldwide.
Sources to corroborate the impact
A. Regional Genetic Laboratory (Manchester, UK) listed on NHS UK Genetic
Testing Network (UKGTN): http://ukgtn.nhs.uk/find-a-test/search-by-laboratory/laboratory/manchester-rgc-36/.
Homepage: www.ukgtn.nhs.uk. UKGTN
provides a search tool for genetic testing services across the UK.
B. ORPHANET, www.orpha.net. The
European portal for rare disease and orphan drugs, receiving 12,000
daily visits. Lists laboratories performing molecular diagnosis of PSACH
C. GENETests, www.genetests.org.
A publicly funded medical genetics information resource developed for
physicians, other healthcare providers, and researchers. Lists
laboratories performing molecular diagnosis of PSACH and/or MED.
D. Email to verify the number of patients tested at GeneDx, Gaithersburg,
E. Email to verify the number of patients tested at Seoul National
University Hospital, Korea.
F. Email to verify the number of patients tested at Regional Genetics
Laboratory, Manchester, UK.
G. EU Committee of Experts on Rare Diseases (EUCERD) report May 2011: http://ec.europa.eu/health/rare_diseases/docs/eucerd2011_report_european_ref_net.pdf
H. ESDN Case Manager, www.esdn.org/eug/Home
and Excel spreadsheets of data analysis.