G: Diagnosis from gene discovery – developmental disorders of eye, brain, nerve and skeleton
Submitting InstitutionUniversity of Edinburgh
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Biological Sciences: Genetics
Medical and Health Sciences: Neurosciences
Summary of the impact
Impact: Health and welfare; policy and guidelines; public
engagement. The identification of >20 genes linked to human
developmental and childhood degenerative disorders.
Significance: Definitive diagnosis is essential for genetic
counselling, prenatal screening and postnatal management.
Beneficiaries: People with developmental disorders and their
families, prospective parents, the NHS and healthcare delivery
organisations; public understanding of genetic disorders.
Attribution: Researchers from UoE identified/characterised all the
genes described, and their mutation in disease.
Reach: Worldwide: these developmental disorders affect thousands
of people. Genetic tests established as a result of the research are
provided for people from 35 countries on all continents.
The development of genetic tests to underpin accurate diagnosis, genetic
counselling and prospective management in developmental disorders
represents a major translational focus for the MRC Human Genetics Unit
(HGU) within UoE.
Developmental disorders are significant clinical problems that result
from perturbation of embryogenesis or early brain development. At least 3%
of live-born babies have a developmental disorder that will have a
deleterious impact on their life. The majority of these disorders are
genetically determined. An understanding of developmental disorders, which
is critical for adequate diagnosis, prognosis and management, requires
both knowledge of the genes involved and how the gene products function as
effectors of the specific developmental processes. The identification and
characterisation of these monogenic disorders exemplifies well the wide
range of impacts that result from apparently "basic" research.
Scientists from the MRC HGU, including Professors David FitzPatrick
(Programme Leader, UoE, 2000-present), Veronica van Heyningen (Programme
Leader, UoE, 1977-2012; now Emeritus), Andrew Jackson (Programme Leader,
UoE, 2005-present) and Peter Brophy (Professor of Anatomy, UoE,
1995-present) have directly contributed to the identification and
functional characterisation of more than 20 genes associated with human
developmental and degenerative disorders. Key examples include:
Eye: Between 2000 and 2012, FitzPatrick and van Heyningen
identified abnormalities in the SOX2, OTX2, PAX6,
STRA6, NF1 and SMOC1 genes as the causes of serious
human eye malformations, notably anophthalmia (absent eye), microphthalmia
(small eye) and coloboma (failure of optic fissure closure) [e.g., 3.1,
3.2]. van Heyningen linked haploinsufficiency of PAX6 to cerebral
malformation and olfactory dysfunction (2001) [3.3] and FitzPatrick
identified SATB2 as the cleft palate gene (2003). FitzPatrick
undertook studies that showed the causative role of mutations in DHCR24
in desmosterolosis, an autosomal recessive disorder of cholesterol
biosynthesis (2001) and in studies that associated disruption of the ST5
gene with mental retardation and multiple congenital anomalies (2010).
Skeleton: More recently, FitzPatrick's work has led to the
identification of mutations in CEP57 that cause mosaic variegated
aneuploidy syndrome (2011), the discovery that gain-of-function mutations
in ARHGAP31, a Cdc42/Rac1 GTPase regulator, cause syndromic cutis
aplasia and limb anomalies (2011), and that a rare intragenic deletion
within the region encoding the NIPBL protein is associated with atypical
facial appearance and growth pattern in Cornelia de Lange Syndrome (2012).
Brain: The work of Jackson since 2005 has been essential to the
identification of seven microcephalic primordial dwarfism genes (ORC1,
ORC4, ORC6, CDT1, CDC6, PCNT and CEP152)
that regulate organism size and cerebral cortex volume [e.g., 3.4].
Jackson and colleagues also showed that mutations in genes encoding the
DNA exonuclease TREX1 and ribonuclease H2 subunits (RNASEH2A, RNASEH2B,
RNASEH2C) cause Aicardi-Goutières syndrome, a congenital immune-mediated
neurodevelopmental disorder [e.g., 3.5].
Nerve: Brophy and colleagues discovered that a mutation in PRX,
encoding periaxin, is responsible for a form of Charcot-Marie-Tooth (CMT)
disease, a disorder of the peripheral nervous system characterised by
progressive loss of muscle tissue and touch sensation (2001) [3.6].
References to the research
The references below represent selected examples from the large body of
3.1 Fantes J, Ragge N, Lynch S,...van Heyningen V, FitzPatrick D.
Mutations in SOX2 cause anophthalmia. Nat Genet. 2003;33:461-3. DOI:
3.2 Ragge N, Brown A, Poloschek C,...Fitzpatrick D, van Heyningen V,
Hanson I. Heterozygous mutations of OTX2 cause severe ocular
malformations. Am J Hum Genet. 2005;76:1008-22. DOI: 10.1086/430721.
3.3 Sisodiya S, Free S, Williamson K,...van Heyningen V. PAX6
haploinsufficiency causes cerebral malformation and olfactory dysfunction
in humans. Nat Genet. 2001;28:214-6. DOI: 10.1038/90042.
3.4 Bicknell L, Bongers E, Leitch A,...Jackson A. Mutations in the
pre-replication complex cause Meier-Gorlin syndrome. Nat Genet.
2011;43:356-9. DOI: 10.1038/ng.775.
3.5 Crow Y, Leitch A, Hayward B,...Jackson A. Mutations in genes encoding
ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic
congenital viral brain infection. Nat Genet. 2006;38:910-6. DOI:
3.6 Guilbot A, Williams A, Ravisé N,... Brophy P, et al. A mutation in
periaxin is responsible for CMT4F, an autosomal recessive form of
Charcot-Marie-Tooth disease. Hum Mol Genet. 2001;10:415-21. DOI:
Details of the impact
Impact on health and welfare and clinical services
Below, three groups of genetic disorders identified and characterised by
UoE researchers, and their specific impact on aspects of clinical
management/service, are described in greater detail. Although rare,
inherited developmental disorders are distributed across the world and are
devastating for patients and their families. Crucially, the identification
of causative mutations permits effective genetic counselling: a
cornerstone of the family management of each of these disorders. UoE
research findings have directly resulted in the availability of clinical
tests (including some offered in-house, see below) to clarify genetic risk
and have enabled diagnostic and/or prenatal testing for these devastating
Genetic testing and pre-natal screening - eye disorders:
Developmental eye disorders occur in approximately five per 10,000 live
births and are responsible for around 25% of severe visual impairments in
childhood. Diagnosis of the primary ocular disorder may be self-evident,
but >50% of cases manifest distinct systemic abnormalities, such as
developmental delay, kidney or heart defects and cleft lip or palate. A
full diagnosis including identification of causative genetic abnormalities
is essential to define the visual potential of the child, inform the
counselling of the parents and establish prospective management, including
the possible need for special educational placement, with respect to the
Tests for mutations in the SOX2, OTX2 and PAX6
genes are now offered by multiple labs in the UK and internationally
including the USA, Germany, France, Denmark and Switzerland [5.1].
Prenatal genetic testing for anomalies in these genes (that allows
informed decision on pregnancy) is offered by some laboratories, e.g.,
GeneDx in the USA. Tests for STRA6, NF1 and SMOC1
gene abnormalities are available in the UK and internationally [5.1].
Molecular diagnosis informing effective clinical management and
counselling - childhood-onset neurological disease: CMT is one of
the most common inherited neurological disorders affecting approximately 1
in 2,500 people, equating to approximately 23,000 people in the UK and
125,000 people in the USA. While Aicardi-Goutières syndrome represents a
rarer disorder, together, these conditions demonstrate the distinct ways
in which clinical diagnosis can be facilitated by accurate genetic
testing. Both conditions are incurable and early diagnosis is instrumental
for clinical management and counselling. Genetic testing for causative
mutations is important in CMT because it does not represent a single
disorder, but a group of conditions that are superficially clinically
similar, but with widely differing modes of inheritance and penetrance.
Effective genetic counselling has only become possible with the
application of genetic testing [5.2]. In contrast, Aicardi-Goutières
syndrome poses a rather different clinical challenge, as it phenocopies
congenital viral infections such as CMV, rubella and transplacentally
acquired HIV. Given the substantial risk of recurrence in subsequent
pregnancies, molecular diagnosis of Aicardi-Goutières syndrome is
essential for counselling and also key to the provision of prenatal
diagnosis in subsequent pregnancies.
Tests for mutations in TREX1, RNASEH2A, RNASEH2B,
RNASEH2C (Aicardi-Goutières syndrome) and PRX (CMT) are
offered in several countries including the UK, USA, Germany, Spain,
Austria, France and Italy [5.1].
Genetic testing to establish effective prospective management - growth
syndromes: Primordial dwarfism is a rare disorder resulting in
extreme pre- and postnatal growth failure, such that people with this
group of conditions are often described as `the smallest people in the
world'. The identification of the genetic basis has had a significant
impact on clinical management. In particular, it has helped to define
those with resulting syndromes who are at risk of insulin-resistant
diabetes mellitus, and of neurovascular complications, enabling specific
targeting of appropriate surveillance [5.3].
Tests for mutations in primordial dwarfism genes are available in the UK,
USA and the Netherlands [5.1]. In the UK they are offered directly by
Jackson's laboratory, and since 2008 Jackson's lab has performed molecular
gene testing on over 400 patients from 35 countries worldwide.
Impact on policy and guidelines
In the report "Genetic ophthalmology in focus: a needs assessment and
review of specialist services for genetic eye disorders" published in
April 2008 (to which FitzPatrick and van Heyningen contributed), the
Foundation for Genomics and Population Health indicated how NHS
ophthalmology services needed to change in response to the opportunities
offered by genetic science. The foundation placed mutation detection in
severe developmental eye disorders on the list of main gaps and perceived
priorities for testing [5.4]. This report has had major impact on UK
Government policy: for example, it was analysed by the House of Lords'
Science and Technology Committee in 2008-2009 [5.5], leading to new
recommendations and improved services. Notably, van Heyningen was an
expert witness to the Committee on April 30th, 2008 [5.5].
Impact on society and public engagement
Genetic testing is recommended by diverse societies and organisations and
is promoted on their websites, e.g., the International Children's
Anophthalmia Network [5.6]. In addition, because people with primordial
dwarfism are among the shortest people in the world, this small group has
a disproportionately large impact on public engagement with developmental
disorders. Primordial dwarfism and its genetic causes have been discussed
in several high-profile television documentaries that generated huge
public interest, e.g., "The Tiniest Boy in Britain" (2011) and "21 and 3ft
tall" (2013). Notably, the latter included an interview with Jackson and
describes research in his lab [5.7].
Sources to corroborate the impact
5.1 Example lists of multiple laboratories from up to 12 countries
providing genetic tests for the genes mentioned in the text. http://www.orpha.net/consor/cgi-bin/index.php
(under: directory of medical laboratories providing diagnostic tests).
Further examples can be found at http://www.ncbi.nlm.nih.gov/gtr/tests/.
5.2 Siskind C, Panchal S, Smith C, et al. A review of genetic counselling
for Charcot Marie Tooth disease (CMT). J Genet Couns. 2013;22:422-36. DOI:
5.3 Semple R, Savage D, Cochran E, et al. Genetic syndromes of severe
insulin resistance. Endocr Rev. 2011;32:498-514. DOI:
5.4 Foundation for Genomics and Population Health (PHG Foundation) report
(April 2008). "Genetic ophthalmology in focus: a needs assessment and
review of specialist services for genetic eye disorders". http://www.phgfoundation.org/file/4199.
5.5 Genomic medicine: 2nd report of session 2008-2009, Volume II:
Evidence. Great Britain Parliament, House of Lords, Science and Technology
5.6 International Children's Anophthalmia Network website. http://www.anophthalmia.org/diagnosis/.
5.7 Daily Mail online (2nd July 2013). "Aged 21 but just 35
inches tall: The man with a rare form of dwarfism which makes him the size
of a three-year-old". http://www.dailymail.co.uk/health/article-2353418/Nick-Smith-The-man-rare-form-dwarfism-makes-size-year-old.html.
[Article about the Channel 5 documentary.]