What testing should be done for relatives of patients known to have an HNF1A or 4A mutation?

1 . Diagnostic HNF1A or 4A genetic testing for relatives with diabetes

Diagnostic genetic testing is advisable for everyone with diabetes in families where an HNF1A or
4A gene mutation has been identified in a family member. This is because making a definitive
diagnosis is important as it will often influence clinical management. Although the chances of the
diabetes being due to the same change in the HNF1A/4A gene is high (around 95%) it is not safe to
assume this, as some families have both MODY and Type 1 or Type 2 diabetes. HNF1A/4A
MODY is frequently misdiagnosed as type 1 diabetes and one UK patient with type 1 diabetes died
in ketoacidosis after being misdiagnosed with MODY that was not confirmed by genetic testing.
Patients with Type 1 or Type 2 diabetes will typically not have a change in the HNF1A/4A gene and
may have specific features like pancreatic autoantibodies or unmeasurable c-peptide levels
associated with Type 1 diabetes or acanthosis nigricans or elevated c-peptide indicating insulin
resistance in Type 2 diabetes.
The different subtypes of HNF1A/4A MODY and Type 1 and Type 2 diabetes all have different
optimal treatment and therefore diagnostic genetic testing will often influence treatment decisions.
In addition the risks of developing diabetes amongst children of Type 1, Type 2 and MODY patients
is also considerably different and confirming MODY by molecular genetic testing can ensure
patients and their families are given appropriate information about their childrens and siblings risk
of developing diabetes.
Testing for a known HNF1A/4A mutation in other family members with diabetes is simpler than
sequencing the entire gene and therefore the costs of testing affected family members is much
reduced (85 as opposed to 350) and may in due course result in treatment changes which could
result in cost savings in the longer term.
To request a diagnostic genetic test in a person with diabetes in a family previously identified with
an HNF1A/4A gene mutation please complete the MODY diagnostic genetic test form
(downloadable from www.diabetesgenes.org and include the name and date of birth of the patient in
whom a diagnosis of HNF1A or 4A MODY has already been confirmed).
2. Relatives not known to have diabetes
It is important that all first degree relatives of a person diagnosed with HNF1A or 4A MODY are
aware that they are at increased risk of developing diabetes. Many relatives will not have been
tested and may have diabetes without realising it and could even have diabetes related
complications present when they are diagnosed. Making an early diagnosis is important so they can
be treated and symptoms and complications prevented. As patients with mutations in HNF1A or 4A
get more hyperglycaemic with age, repeated testing over time is needed, especially in children and
young adults. Mutation carriers may have normal glucose tolerance as young children.
Who should test?
Testing of the degree of glycaemia should be set up by the individual either on their own (eg home
urine testing for glucose) or with their GP so they can get tested regularly and receive the results
easily.
When should relatives be tested?
In general testing should take place whenever symptoms of diabetes occur eg thirst or polyuria, or
at least annually in the absence of symptoms after the age of 6 years.

What type of test?

The type of testing varies between individuals depending on their type of mutation, age and
individual request. In children in HNF1A families most would recommend urine analysis screening
for glucose. In all patients a diagnosis of diabetes will need blood being taken for a plasma glucose
patients own testing should not be used for diagnosis.
Guidelines for the different types of testing follow:
Oral glucose
tolerance test
(OGTT)

Fasting glucose
Urine glycosuria

Genetic testing for

mutation

The best screening test advisable in

patients thought to be at high risk eg
those with symptoms, glycosuria, a
high random blood or plasma
glucose > 7.8 or a fasting glucose
>5.5 mmol/l
Can be diagnostic late in the
hyperglycaemia progression but not
sensitive
In patients with HNF1A low renal
threshold means that urine testing
after a high glucose load is a
sensitive screening test (Stride A
Diabetes Care 2005). Good for
children screening with OGTT then
performed if glycosuria positive
Should only be done after testing for
glycaemia. If diabetic then should
be done as a diagnostic test (see
above). If not diabetic then whether
a predictive test should be
performed is up to the individual
involved. Predictive testing should
only be performed if the patient is
keen for this after genetic
counselling. Testing of children
before they are 16 years needs
careful consideration. and we
recommend referral to the local
clinical genetics service in these
cases.

Diagnostic of diabetes 2 hr plasma

glucose (PG) > 11.2 mmol/l.
Impaired Glucose tolerance (IGT) 2 hr
PG 7.8 11.1
Diagnostic of diabetes FPG >7.0 mol/l,
if > 5.5 mol/l proceed to OGTT
Not diagnostic on its own but
indicative of plasma glucose exceeding
8 9 mol/l in HNF1A but considerably
higher in HNF4A.

Will not on its own make a diagnosis

of diabetes but finding of a mutation
will result in a lifetime risk of diabetes
of >95%. Failure to find a mutation
means they will not develop MODY.