Download Fanconi-Bickel Syndrome - UK Genetic Testing Network

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier
Test – Disease – Population Triad
Disease – name
Fanconi-Bickel syndrome
OMIM number for disease
227810
Disease – alternative names
please provide any alternative names
you wish listed
Glycogen storage disease type XI
Disease – please provide a brief
description of the disease
characteristics
Fanconi-Bickel syndrome is a disorder of carbohydrate
metabolism caused by mutations in SLC2A2. FanconiBickel syndrome presents in early infancy and is
characterised by the association of hepatomegaly,
hypoglycaemia and severe hypophosphataemic rickets
and marked growth retardation due to proximal renal
tubular dysfunction.
Autosomal recessive
Disease - mode of inheritance
Gene – name(s)
Solute Carrier family 2 (Facilitated Glucose Transporter)
Member 2; SLC2A2
OMIM number for gene(s)
138160
Gene – alternative names
please provide any alternative names
you wish listed
Glucose transporter protein 2 (GLUT2)
Gene – description(s)
number of amplicons).
(including SLC2A2: Genomic Size: 30623; Exon count 11; Coding
Exon count 11 (sequence amplicons 11)
Mutational spectrum for which you
test including details of known
common mutations.
Missense, splicing, regulatory, small
insertions, indels and gross insertions.
deletions,
Technical Method (s)
Sequencing of the entire coding region and conserved
splice sites.
Validation Process
Sequence analysis was carried out on two patients with
a suspected diagnosis of Fanconi-Bickel syndrome.
Note: please explain how this test has
been validated for use in your
laboratory
Are you providing this test already?
If yes, how many reports have you
produced?
Yes: Testing has been carried out on two patients. One
patient was positive for an SLC2A2 mutation and carrier
testing was carried out on two family members. Three
reports have been issued to date.
Please give the number of mutation
positive/negative samples you have
reported
1
For how long have you been
providing this service?
Is there specialised local
clinical/research expertise for this
disease?
Are you testing for other
genes/diseases closely allied to this
one? Please give details
Since June 2008
Yes
No
Please provide details
Genetics of diabetes research group led by Prof. Andrew
Hattersley
Yes: KCNJ11, ABCC8, HNF4A, GCK, HADH and
GLUD1 mutations can cause hypoglycaemia. PHEX,
FGF23, DMP1 and SLC34A3 mutations can cause
hypophosphataemic rickets.
Index cases: <5 tests
Your Activity
If applicable - How many tests do you
Family members where mutation is known: <10 tests
currently provide annually in your
laboratory?
Index cases: at least anticipated national test volume
Your Activity
How many tests will you be able to
Family members where mutation is known: at least
provide annually in your laboratory if
anticipated national test volume
this gene dossier is approved and
recommended for NHS funding?
Based on experience how many tests Index cases:
will be required nationally (UK wide)?
Family members where mutation is known:
Please identify the information on which
this is based
Not applicable
National Activity
(England, Scotland, Wales &
Northern Ireland)
If your laboratory is unable to provide
the full national need please could you
provide information on how the national
requirement may be met. For example,
are you aware of any other labs
(UKGTN members or otherwise)
offering this test to NHS patients on a
local area basis only? This question
has been included In order to gauge if
there could be any issues in equity of
access for NHS patients.
It is
appreciated that some laboratories may
not be able to answer this question. If
this is the case please write “unknown”.
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Epidemiology
Estimated prevalence of
disease in the general UK
population
Please identify the information
on which this is based
Estimated gene frequency
(Carrier frequency or allele
frequency)
No epidemiological data are available
This is a rare syndrome and no accurate estimates of prevalence
have been published. Cases without a family history or with
variant presentation are likely to have been under reported so the
true incidence may be higher than is currently perceived.
Unknown
Please identify the information
on which this is based
Estimated penetrance
Please identify the information
on which this is based
Highly penetrant – no unaffected siblings known to be
homozygous or compound heterozygous for SLC2A2 mutations.
Target Population
Fanconi-Bickel syndrome has been described in Caucasian
(British, Austrian, Swiss, German, French, Italian, Polish, Turkish,
Israeli), Arabian countries of the Near East and North Africa
(Algerian, Moroccan, Sudanese, Jordanian, Libyan) and North
America. Testing will be available for affected cases with a
clinical diagnosis and carrier testing for family members (Santer et
al Eur J Pediatr 1998, 157: 783-797).
Description of the population
to which this test will apply (i.e.
description of the population
as defined by the minimum
criteria listed in the testing
criteria)
Estimated prevalence of
disease in the target
population
Unknown
Intended Use (Please use the questions in Annex A to inform your answers)
Please tick the relevant clinical purpose of testing
YES
Diagnosis

Treatment

Prognosis & Management

NO

Presymptomatic testing
Risk Assessment for family members

Risk Assessment – prenatal testing

3
Test Characteristics
Analytical sensitivity and
specificity
Single direction sequence analysis using Mutation Surveyor
software. Sensitivity 99% and specificity 99% (in-house data)
This should be based on your
own laboratory data for the
specific test being applied for or
the analytical sensitivity and
specificity of the
method/technique to be used in
the case of a test yet to be set
up.
Missense, splicing, regulatory, small deletions, insertions, indels
and gross insertions have been reported.
SLC2A2 mutations are distributed throughout the gene with no
apparent clustering or mutation hot spots.
If more than one gene will be
tested, please include your
testing strategy and data on the
expected proportions of positive
results for each part of the
process. Please illustrate this
with a flow diagram.
>99%
Fanconi-Bickel syndrome is a well-defined clinical entity
characterized by hepatorenal glycogen accumulation, Fanconi
nephropathy and impaired metabolism of glucose and
The clinical sensitivity of a test is galactose. Typical clinical finding include hepatomegaly
secondary to glycogen accumulation, glucose and galactose
the probability of a positive test
result when disease is known to intolerance, fasting hypoglycaemia, characteristic tubular
be present; the clinical specificity nephropathy, rickets and marked growth retardation. This
disease is associated with mutations in the SLC2A2 gene in
is the probability of a negative
many
ethnic groups, indicating that Fanconi-Bickel syndrome is
test result when disease is
a
single
gene disease.
known to be absent. The
denominator in this case is the
number with the disease (for
Out of the 110 cases reported worldwide with a clinical
sensitivity) or the number
diagnosis of Fanconi-Bickel syndrome only one patient did not
without disease (for specificity)
have a mutation in the coding region of the SLC2A2 gene.
However it was noted that heterozygous long range deletions
and mutation in the introns were not excluded in this patient.
(Santer et al Eur J Pediatr 1998, 157: 783-797, Ozer et al
Pediatr Nephrol 2003 18:397-398).
Clinical sensitivity and
specificity of test in target
population
Clinical validity (positive and
negative predictive value in
the target population)
The clinical validity of a genetic test is a
measure of how well the test predicts
the presence or absence of the
phenotype, clinical disease or
predisposition. It is measured by its
positive predictive value (the probability
of getting the disease given a positive
test) and negative predictive value (the
probability of not getting the disease
given a negative test).
The SLC2A2 mutations known to date (Missense, splicing,
regulatory, small deletions, insertions, indels and gross
insertions) result in a functional loss of the monosaccharide
transporter SLC2A2 which is compatible with the clinical
symptoms observed in patients with Fanconi-Bickel syndrome.
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Molecular analysis of the SLC2A2 gene in individuals with a
clinical diagnosis of Fanconi-Bickel syndrome will allow a definitive
diagnosis. Also due to the occurrence of severe cases of FanconiBickel syndrome, parents of a severely affected child may
consider prenatal testing. Prenatal testing can be offered once the
Please provide a description molecular diagnosis is confirmed.
of the clinical care pathway.
Clinical utility of test in
target population
(Please refer to Appendix A)
How will the test add to the
management of the patient or
alter clinical outcome?
The identification of a SLC2A2 mutation will provide a definite
diagnosis of Fanconi-Bickel syndrome which allows appropriate
symptomatic replacement treatment (supplementation of water,
electrolytes, and vitamin D, restriction of galactose, and a diabetes
mellitus-like diet, presented in frequent small meals with adequate
caloric intake) which may improve the growth and well-being of the
patient.
What impact will this test have
on the NHS i.e. by removing
the need for alternative
management and/or
investigations for this clinical
population?
Is there an alternative means
of diagnosis or prediction that
does not involve molecular
diagnosis? If so (and in
particular if there is a
biochemical test) please state
the added advantage of the
molecular test
Alternative methods of diagnosis involve endocrine,to look for
ketonuria in the fasting state as well as hyperglycaemia in the
postabsoptive state, liver histology to determine steatosis and
storage of excessive amounts of glycogen, renal function tests to
determine
glucosuria,
hyperphosphaturia,
hyperuricaemia,
hyperaminoaciduria
and
Proteinuria.
Ophthalmological
examination to determine the presence of cataracts and bone
mineral density tests to determine osteoporosis.
The identification of a SLC2A2 mutation will provide a definite
diagnosis of Fanconi-Bickel Syndrome which allows appropriate
treatment.
Please describe any specific
ethical, legal or social issues
with this particular test?
Not applicable
Please complete the testing criteria form.
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UKGTN Testing criteria
Name of Disease(s): Fanconi-Bickel Syndrome; FBS (227810)
Name of gene(s):SLC2A2 (138160)
Patient name:
Date of birth:
Patient postcode:
NHS number:
Name of referrer:
Title/Position:
Lab ID:
Referrals will only be accepted from one of the following:
Referrer
Clinical Genetics
Tick if this refers to you.
Minimum criteria required for testing to be appropriate as stated in the Gene
Dossier:
Criteria
Tick if this
patient meets
criteria
Young infants with:
 Hepatomegaly secondary to glycogen
accumulation AND
 Glucose and Galactose intolerance AND
 Fasting hypoglycaemia AND
 Fanconi nephropathy (proximal renal
tubular dysfunction) AND
(in later infancy/childhood) one of:
 Hypophospataemic rickets
 Generalised osteopenia
 Growth retardation
OR Family members with an identified mutation
OR Prenatal testing where the family mutation
has already been identified
If the sample does not fulfil the clinical criteria or you are not one of the specified
types of referrer and you still feel that testing should be performed please contact the
laboratory to discuss testing of the sample.
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