Download Glucose-Galactose Malabsorption

Proposal form for the evaluation of a genetic test for NHS Service
Gene Dossier
Test – Disease – Population Triad
Disease – name
Congenital Glucose-Galactose Malabsorption
OMIM number for disease
606824
Disease – alternative names
please provide any alternative names
you wish listed
MONOSACCHARIDE MALABSORPTION; GM
Disease – please provide a brief
description of the disease
characteristics
Glucose-Galactose Malabsorption presents within the first weeks
of life with severe watery and acidic diarrhoea and dehydration.
The disorder can be fatal within a few weeks unless glucose and
galactose are eliminated from the diet. Patients may also present
with neonatal or early onset diabetes.
Disease - mode of inheritance
Autosomal recessive
Gene – name(s)
SLC5A1
OMIM number for gene(s)
182380
SOLUTE CARRIER FAMILY 5 (SODIUM/GLUCOSE
COTRANSPORTER), MEMBER 1
SODIUM-GLUCOSE TRANSPORTER 1; SGLT1
SODIUM-GLUCOSE COTRANSPORTER, INTESTINAL
NA+/GLUCOSE COTRANSPORTER, HIGH AFFINITY; NAGT
Gene – description(s) (including Located on 22q13.1; size: 71.39Kb; 15 coding exons (15
amplicons).
number of amplicons).
Gene – alternative names
please provide any alternative names
you wish listed
Mutational spectrum for which you Missense, nonsense,
test including details of known mutations.
common mutations.
splicing
and
small
insertion/deletion
Technical Method (s)
Sequencing of the entire coding region and conserved splice
sites.
Validation Process
Sequence analysis of the coding region and splice sites has been
carried out for 1 patient. Sequence analysis for the identification
of heterozygous and homozygous mutations is employed for
screening of >30 genes in the laboratory.
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?
Please give the number of mutation
positive/negative samples you have
reported
Yes
If Yes:
Number of reports issued: 1
Number of reports mutation positive: 1
Number of reports mutation negative:
1
Approval Date: Sept 2010
Submitting laboratory: Exeter Molecular Genetics
Copyright UKGTN © 2010
For how long have you been
providing this service?
Since February 2010
Is there specialised local
clinical/research expertise for this
disease?
Yes 
Are you testing for other
genes/diseases closely allied to
this one? Please give details
No
Please provide details
Genetics of diabetes research group led by Prof. Andrew
Hattersley.
Yes. Testing is offered for monogenic forms of diabetes and
hyperinsulinism.
Index cases: N/A
Your Current Activity
If applicable - How many tests do you
Family members where mutation is known: N/A
currently provide annually in your
laboratory?
Your
Capacity if Gene Dossier Index cases: unlimited
approved
Family members where mutation is known: unlimited
How many tests will you be able to
provide annually in your laboratory if
this gene dossier is approved and
recommended for NHS funding?
Based on experience how many Index cases: <5 tests. Population studies in the UK have not been
tests will be required nationally (UK carried out.
wide)?
Family members where mutation is known: <5 tests.
Please identify the information on
which this is based
Unknown
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”.
2
Approval Date: Sept 2010
Submitting laboratory: Exeter Molecular Genetics
Copyright UKGTN © 2010
Epidemiology
Estimated prevalence of disease in
the general UK population
Rare- approximately 200 cases worldwide (Wright, Am J Physiol
1998, 275: 879-882). Accurate data is not available for the UK.
Please identify the information on
which this is based
Estimated gene frequency
(Carrier frequency or allele frequency)
Unknown.
Please identify the information on
which this is based
Estimated penetrance
Please identify the information on
which this is based
100% penetrance in 26 families studied (Martin et al, Nat Genet
1996, 12: 216-220)
Mutations have been identified in British, French, Dutch, Belgium,
African, Hispanic and Japanese families. Test will be used for all
affected individuals with a clinical diagnosis of suspected
Description of the population to which glucose/galactose malabsorption presenting in the neonatal
this test will apply (i.e. description of period or early onset of neonatal diabetes and carrier testing
the population as defined by the offered to relatives.
minimum criteria listed in the testing
criteria)
Target Population
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
Approval Date: Sept 2010
Submitting laboratory: Exeter Molecular Genetics
Copyright UKGTN © 2010
Test Characteristics
An a lytic a l s e n s itivity a n d s p e c ificity
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.
Single direction sequence analysis using Mutation
Surveyor software - sensitivity 99% and specificity 99%
(in-house data).
Clinical sensitivity and specificity of
test in target population
Martin et al (1996) analysed the SLC5A1 gene in 30 affected
individuals from 26 families. Homozygous mutations were
identified in 16 families, 7 families were compound heterozygote
and in 3 families only one mutation was detected. Mutations
identified include missense, nonsense, frameshift and splicing.
Mutations were shown to affect conformation of the
sodium/glucose transporter affecting either trafficking to the
plasma membrane or its function as a cotransporter. (Martin et
al, Nat Genet 1996, 12: 216-220)
The clinical sensitivity of a test is the
probability of a positive test result when
disease is known to be present; the
clinical specificity is the probability of a
negative test result when disease is
known to be absent. The denominator
in this case is the number with the
disease (for sensitivity) or the number
without disease (for specificity)
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).
Glucose-Galactose Malabsorption produces a clinical picture
similar to that of intestinal disaccharidase deficiency (Congenital
Sucrase-Isomaltase Deficiency, OMIN 222900) caused by
mutations in the Sucrase-Isomaltase gene. However the median
age at the onset of watery diarrhea is later at 3 weeks (range, 2
to 16 weeks) and that the diarrhoea can persist for many
months (Newton et al, J Pediat 1996, 128: 753-756).
Testing pathway
Please include your testing strategy if
more than one gene will be tested and
data on the expected proportions of
positive results for each part of the
process. Please illustrate this with a
flow diagram. This can be added to the
document as a separate sheet if
necessary.
4
Approval Date: Sept 2010
Submitting laboratory: Exeter Molecular Genetics
Copyright UKGTN © 2010
Clinical utility of test in target
population
(Please refer to Appendix A)
Molecular analysis of the SLC5A1 gene in individuals with a
clinical diagnosis of Congenital Glucose-Galactose Malabsorption
will allow a definitive diagnosis. A molecular diagnosis will then
provide means by which carrier testing can be offered to relatives
and offspring at risk. Prenatal testing can be offered once the
Please provide a description of the molecular diagnosis is confirmed. Those affected with the disorder
clinical care pathway.
can then be given appropriate treatment.
How will the test add to the
management of the patient or alter
clinical outcome?
Identifying affected patients who are SLC5A1 gene mutation
carriers will allow treatment to be started immediately. Treatment
involves complete elimination of glucose and galactose from the
diet. Fructose and xylose are absorbed normally so fructose
based formula are well tolerated by patients and leads to a
dramatic improvement. Children thrive on fructose replacement
formulas but symptoms return even in adulthood with as little as
6g of glucose.
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? Please provide evidence
from your own service.
Definitive diagnosis allows appropriate treatment of the affected
individuals and will allow treatment to be started sooner,
potentially avoiding the patient being cared for in a neonatal unit.
What are the consequences of not
doing this genetic test.
Commissioners have asked for
specific information to support
introduction of tests.
Potential fatal diarrhoea and dehydration in patients and affected
siblings.
Utility of test in the NHS
In a couple of sentences explain the
utility of this test for the disease(s)
Molecular analysis of the SLC5A1 gene in individuals with a
clinical diagnosis of Congenital Glucose-Galactose Malabsorption
will allow a definitive diagnosis and allow appropriate treatment to
be given.
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
Diagnosis of Glucose-Galactose Malabsorption can be made by
H 2 breath test (oral administration of glucose or galactose results
in breath H 2 elevation greatly above 20 parts/million). The patient
is given a small amount of pure lactose (typically 2g/kg), and
breath readings are taken every 15, 30 or 60 minutes for two to
three hours. Test is performed in duplicate. A molecular test will
be quicker and easier to perform and will allow carrier testing for
other family members.
Please describe any specific ethical,
legal or social issues with this
particular test?
Not applicable
5
Approval Date: Sept 2010
Submitting laboratory: Exeter Molecular Genetics
Copyright UKGTN © 2010
UKGTN Testing criteria
Name of Disease(s): GLUCOSE/GALACTOSE MALABSORPTION; GGM (606824)
Name of gene(s): solute carrier family 5 (sodium/glucose cotransporter), member 1;
SLC5A1 (182380)
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
Consultant Clinical Geneticist
Consultant Paediatrician/
Consultant Neonatologist
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
Clinical diagnosis of Congenital Glucose-Galactose
Malabsorption presenting in the neonatal period AND
Family history strongly suggestive for recessive
inheritance OR
Family members of affected individuals with a
known mutation in a primary or secondary degree
relative
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.
6
Approval Date: Sept 2010
Submitting laboratory: Exeter Molecular Genetics
Copyright UKGTN © 2010