Case Study 5: Improving screening, diagnosis and treatment of inherited blindness and deafness
Submitting InstitutionUniversity of Leeds
Unit of AssessmentPsychology, Psychiatry and Neuroscience
Summary Impact TypeTechnological
Research Subject Area(s)
Biological Sciences: Genetics
Medical and Health Sciences: Neurosciences
Summary of the impact
Researchers at the University of Leeds (UoL) have identified mutations in
key genes which are major causes of deafness and blindness. Mutations in GJB2,
identified in a Leeds/London collaboration, are the most common cause of
human inherited deafness, affecting millions worldwide, and Leeds
researchers have also highlighted 13 key genes involved in inherited
blindness, accounting for an estimated 5% of around 2 million people
throughout the world with inherited eye diseases. This work has led to the
availability of vital genetic testing, enabling early diagnosis, better
management and improving outcomes for patients, as well as better
counselling and prenatal screening for families.
Researchers at the UoL use family studies to track down mutations causing
human inherited diseases. Families of all ethnicities and inheritance
types are studied. In particular high rates of consanguineous marriage in
the West Yorkshire Pakistani community have created a local healthcare
challenge in the form of increased risk of recessively inherited diseases.
Such families are amenable to autozygosity mapping, a technique piloted
and developed by UoL geneticists using a pipeline of in-house software. To
date research in Leeds has identified more than 40 genes mutated in
different inherited diseases, many of them tracked down by autozygosity
The first success for autozygosity mapping in Leeds was in non-syndromic
deafness, through the Leeds Deafness Research Group set up by Professor
Mueller (Consultant Clinical Geneticist at the Yorkshire Regional Genetics
Service (YRGS), 1990-present, Professor 1993 until retirement through ill
health in 2001, UoL) [i-ii] and Dr. Lench (Senior Lecturer,
1994-99, UoL). By pooling genetic data from families with collaborators at
St Bartholomew's, London, they showed that mutations in the GJB2
gene cause autosomal recessive deafness  (873 cites). Over the
next four years, the Leeds group, working with international
collaborators, characterised the two most common mutations found and
defined the spectrum of GJB2 mutations in patients with inherited
deafness  (178 cites). Their work showed that GJB2
mutations account for around 60% of all inherited prelingual non-syndromic
Inspired by this, Professor Inglehearn (Senior Wellcome Fellow
1997-2002; Professor of Molecular Ophthalmology 2001-present, UoL) and Mr
McKibbin (Consultant Ophthalmologist at St. James University
Hospital, 2001-present; Honorary Senior Lecturer/Associate Professor,
2001-present, UoL) established the Leeds Vision Research Group [iii-iv].
They have used similar techniques in collaborative research, much of it
led from Leeds, to identify 13 proteins (RP1, PRPF8, PRPF3, PAP1/RP9,
ADAM9, CNNM4, LTBP2, LCA5/lebercilin, ATOH7, LRP5, TSPAN12, SLC4A11 and
PXDN) mutated in eye diseases.
An early key Leeds finding was mutations in pre-mRNA splicing factors,
including PRPF8  (133 cites), PRPF3 and PAP1/RP9, in dominant
retinitis pigmentosa. These were the first three of a series of
spliceosome components implicated in inherited blindness, highlighting a
new disease pathway.
Another mechanism uncovered by Leeds in collaboration with others is the
finding that retinal degeneration can result from cilia defects. As
co-leaders of an international consortium Inglehearn and
colleagues identified mutations in lebercilin causing a rare inherited eye
disease, Leber congenital amaurosis  (70 cites), with Leeds
making the initial discovery. Inglehearn also supplied genetic
data and a key genetically-linked family, contributing substantially to
the identification of mutations in RP1 as a cause of dominant retinitis
pigmentosa  (114 cites). Both proteins are cilia components.
The Leeds Vision Research Group leads international research into retinal
vascular diseases and has identified mutations in LRP5  (147
cites) and TSPAN12 as common causes of familial exudative
vitreoretinopathy (FEVR) - a condition which mimics retinopathy of
prematurity seen in premature babies. These and other FEVR genes are
components of the Norrin Beta-catenin signalling pathway, showing that
this pathway regulates retinal blood vessel formation.
References to the research
 Kelsell, D.P., ... Lench*, N.J., ... Mueller*, R.F., &
Leigh, I.M. (1997). Connexin 26 mutations in hereditary non-syndromic
sensorineural deafness. Nature, 387, 80-83. doi: 10.1038/387080a0
The first report of mutations in connexin26 (GJB2) causing prelingual
deafness in both dominant and recessive families.
 Scott, D., Kraft, M., ... Markham*, A.F., Mueller*, R.F.,
Lench*, N.J., ... Smith, R.J., & Sheffield, V.C. (1998).
Identification of mutations in the connexin 26 gene that cause autosomal
recessive nonsyndromic hearing loss. Human Mutation, 11, 387-94.
doi: 10.1002/(SICI)1098-1004(1998)11:5 Research showing the full
spectrum of mutations in this gene and high frequency of these mutations
as a cause of inherited deafness.
 McKie*, A.B., McHale*, J.C., Keen*, T.J., Tarttelin*, E.E.,...
A.C., Markham*, A.F. & Inglehearn*, C.F. (2001). Mutations in
the pre-mRNA splicing factor gene PRPF8 cause autosomal dominant retinitis
pigmentosa (RP13). Human Molecuar Genetics, 10, 1555-62. doi:
The finding of heterozygous mutations in the first of a series of mRNA
splicing factors essential to every cell, yet which cause only inherited
 den Hollander, A., ... Mohamed*, M.D., Arts, H.*, ... Towns*,
K., ... McKibbin*, M., ... Ivings*, L., Williams*, G.A.,
Springell*, K., Woods*, C.G., Jafri*, H., ... Inglehearn*,
C.F., & Roepman, R. (2007). Mutations in LCA5, encoding the
ciliary protein lebercilin, cause Leber congenital amaurosis. Nature
Genetics, 39, 889-95. doi: 10.1038/ng2066
Research identifying mutations in an as yet uncharacterised protein
causing inherited blindness plus evidence that it is a component of the
 Sullivan, L.S., ... Hide, W.A., Gal, A., Denton, M., Inglehearn*,
C.F., Blanton, S., & Daiger, S.P. (1999). Mutations in a novel
retina-specific gene cause autosomal dominant retinitis pigmentosa. Nature
Genetics, 22, 255-59. doi: 10.1038/10314
Study describing mutations in an as yet uncharacterised protein, plus
evidence that this is a component of the primary cilium.
 Toomes*, C., Bottomley*, H., ... Bruffell*, K., Scott*, S.,
... Markham*, A. F., Downey*, L., & Inglehearn*, C.F. (2004).
Mutations in LRP5 or FZD4 underlie the common FEVR locus
on chromosome 11q13. American Journal of Human Genetics, 74,
721-30. doi:10.1086/383202 Paper showing that defects in LRP5, as well
as causing osteoporosis/pseudoglioma syndrome, also cause potentially
blinding retinal vascular defect FEVR.
Key Funding and Grants
[i] European Union Collaborative Award. (2000-2002). Human
Hereditary Deafness. Mueller*, R.F. €245,774.
[ii] Royal National Institute for the Deaf. (2000-2003). Causes of
Progressive age-related hearing loss. Co-PI- Mueller*, R.F. £110,422.
[iii] Wellcome Trust Senior Fellowship. (1997-2002). The
identification and characterisation of genes involved in autosomal
dominant retinitis pigmentosa. Inglehearn*, C.F. £963,917.
[iv] Sir Jules Thorn Trust award. (2010-1014). Identification of
recessive disease genes in consanguineous families. Co-PI: Inglehearn*,
Note: All UoA4 researchers in bold; *research conducted by
academics at the UoL.
Details of the impact
Identification of previously unknown gene mutations in Leeds has had a
major impact on diagnosis, management and screening for affected families.
Findings have also opened the way for better understanding of the causes
of inherited blindness and deafness and potential treatments.
Impact on health and welfare: Inherited deafness
Approximately seven million people worldwide have inherited deafness, and
of these around three million have deafness due to GJB2 mutations.
Prior to the discovery that GJB2 mutations cause inherited
deafness, it was impossible to carry out genetic testing in patients. Our
work alongside international collaborators has enabled clinical genetics
laboratories to provide testing and unequivocal genetic counselling for
deaf individuals around the world during the period 2008-13.
As well as publishing, Professor Mueller worked with YRGS colleagues to
develop a diagnostic service screening for GJB2 mutations. There
has been high demand for this locally due to the frequency of GJB2
mutations within the local Pakistani population. Furthermore, in 2002 they
submitted details of the reagents and protocols used in screening GJB2 to
the UK Genetic Testing Network portfolio. Other laboratories around the
world used the published information to set up their own GJB2
screening services. In all, 353 laboratories offering molecular genetics
testing are listed on the Orphanet web site, which is primarily European,
while the Genetests website lists over 600 such laboratories, with a
greater emphasis on laboratories from the US and elsewhere (data confirmed
19/9/13). There is little overlap, with laboratories tending to list on
one site or the other, and neither list is comprehensive. It therefore
seems likely that over 1000 laboratories around the world offer genetic
testing. Of these, 268 offer a screen for GJB2 [A]. We
surveyed 15 of these, including 4 UK, 2 US, 10 European and 1 Israeli
laboratories, which stated that they carry out a total of around 1340 GJB2
tests per year. Using figures based largely on 2012 [B] we infer
that as many as 24,000 GJB2 screens are carried out internationally per
For patients with genetic disease, a delay in diagnosis is one of the
principal barriers to appropriate care [C]. The availability of
genetic testing significantly improves outcomes for deafness, one of the
most common abnormalities present at birth. A child with undetected
hearing loss is at risk of failing to develop normal speech and language
and acquiring the cognitive abilities needed to access education [D].
Presymptomatic identification of children with inherited hearing loss,
only possible through genetic testing in high-risk families, permits the
fitting of hearing aids at a very early age, which significantly improves
outcome [E]. It also facilitates the learning of speech skills and
training in lip reading and/or British Sign language.
Impact on health and welfare: Retinal dystrophy
Around two million people are affected by retinal dystrophy worldwide and
the 13 genes identified in Leeds over the period 1999 to 2013, which
include RP1 (1999), PRPF8 (2001), LRP5 (2004) and LCA5 (2007), may account
for around 5%. With partial gene lists it is difficult to determine the
cause in such a heterogeneous disease, so finding new genes not only
benefits patients with mutations in these genes but also makes it easier
to interpret results in all patients, including those with mutations in
other known retinal dystrophy genes. Our work, done in international
collaboration, has led to vital genetic tests enabling diagnosis and
appropriate counselling. We worked directly with YRGS to develop a
screening service, providing primers, protocols and expertise. In 2008 we
also submitted a gene dossier of diagnostic information on LRP5 mutations
to the UK Gene Testing Network (the document can be retrieved from
to facilitate the development of genetic testing for FEVR throughout the
UK. The Orphanet and Genetests websites list 45 laboratories worldwide
that test for retinal dystrophies [A]. We contacted these and 6
responded, including 2 UK and 4 European, stating that they do 2995 tests
per year for PRPF8 (659), RP1 (1329), LRP5 (360) and LCA5 (647) [B].
These figures imply that perhaps as many as 22,000 screens for these genes
were done in 2012 internationally [B].
Qualitative research with retinal dystrophy patient groups by McKibbin
indicates that families place a high value on knowing the cause of their
condition and regard this information as potentially life-changing [F].
Genetic testing currently identifies mutation(s) in 50-70% of patients,
including ~5% with mutations in the genes identified in Leeds. Knowing the
exact gene and mutation allows clinicians to give their patients a clear
prognosis, including likely progression and complications and clarifying
mode of inheritance.
In addition, in a growing number of cases, treatment can be improved in
light of the genetic diagnosis. Some retinal dystrophies are treatable
with dietary or other interventions. Diagnosis of a ciliopathy [4, 5]
points to a need to assess kidney function [G]; an FEVR diagnosis
 has implications for risk of osteoporosis and indicates bone
density scanning [H]. Genetic diagnosis can also lead to gene or
mutation-specific therapies. There are now 16 different therapies for
inherited blindness undergoing clinical trials around the world [I].
Importance for families
The complex nature of genetic disease means that families and clinicians
place a premium on simple diagnostic tests [J]. Couples planning a
family can be given accurate recurrence risks, and unaffected members can
request confidential testing of genetic status. Genetic counselling is of
particular relevance in the Pakistani community, where arranged marriage
to a relative is the norm, increasing risk of recessive disease. Raised
awareness of the consequences of consanguinity may lead to changes in
reproductive practise and thus reduce incidence of these conditions. The
Leeds Genetics grouping held quarterly meetings in Bradford 2010-12 with
patients, parents and families, patient advocacy groups and interested
healthcare professionals to discuss these issues.
Sources to corroborate the impact
[A] Orphanet. A database of genetic tests provided by European
Genetests. A partial list of additional genetic screening services
throughout the world: http://www.genetests.org
[B] Postal survey of all laboratories offering screening for GJB2
mutations listed on the Genetests and Orphanet Websites together with
individual responses. Includes service review documents from the Head of
YRGS Laboratory, on numbers tested in Yorkshire
[C] Rare Disease UK. (2010). Experiences of rare diseases: An
insight from patients and families (pp. 8, 9). Retrieved from http://www.raredisease.org.uk/documents/RDUK-Family-Report.pdf
[D] Public Health England's NHS Newborn Hearing Screening
Programme. Retrieved from http://hearing.screening.nhs.uk/nationalprog
[E] Anderson, I., Weichbold, V., D'Haese, P.S., Szuchnik, J.,
Quevedo, M.S., ... Dieler, W.S., & Phillips, L. (2004). Cochlear
implantation in children under the age of two-what do the outcomes show
us? International Journal of Pediatric Otorhinolaryngology, 68,
425-31. doi: 10.1016/j.ijporl.2003.11.013
[F] Bong, C., Potrata, B., Hewison, J., & McKibbin, M.
(2010). Attitudes of patients and relatives/carers towards genetic testing
for inherited retinal disease. Eye, 24, 1622-25. doi:
[G] Waters, A.M., & Beales, P.L. (2011). Ciliopathies: an
expanding disease spectrum. Pediatric Nephrology, 26, 1039-56.
[H] Qin, M., Hayashi, H., Oshima, K., Tahira, T., Hayashi, K.,
& Kondo, H. (2005). Complexity of the genotype-phenotype correlation
in familial exudative vitreoretinopathy with mutations in the LRP5 and/or
FZD4 genes. Human Mutation, 26, 104-12. doi: 10.1002/humu.20191
[I] Boye, S.E., Boye, S.L., Lewin, A.S., & Hauswirth, W.W.
(2013). A comprehensive review of retinal gene therapy. Molecular
Therapy, 21, 509-19. doi: 10.1038/mt.2012.280
[J] Testimonials are available on the value of Leeds' gene
discovery research to patient groups, Clinicians and NHS Genetics
laboratories (24.6.13- 8.11.13).