Identifying monogenic diabetes Agnieszka Graja RGN, MSc Genetic Diabetes Nurse 7th November 2016

What might suggest your patient has monogenic diabetes ? Diabetes diagnosed <6 months of age Diabetes diagnosed below 25 years of age and a parent with diabetes Diabetes plus e.g. RCAD, MIDD, DEND What else might help determine whether your patient has monogenic diabetes ?

Islet antibodies 508 MODY patients and 98 newly diagnosed Type 1 Costs £20, new cut offs established in 500 controls. Those GAD + with MODY may reflect 1-2% of normal population who are antibody +. GAD and IA2 both automated standardised tests through accredited lab (high quality) McDonald T et al (2011) Diabet Med 3

UCPCR can aid differentiate between Type 1 and MODY Urinary C-Peptide Creatinine Ratio UCPCR: Most useful outside honeymoon period, post prandial sample can be posted <0.2 nmol/mmol indicates insulin deficiency Besser R et al (2011) Diabetes Care

www.diabetesgenes.org

Example in practice Insulin treated from diagnosis 0.7% Female Probability of MODY Insulin treated from diagnosis 0.7% Female Diagnosed age 19, now 30 Parent with diabetes HbA1c 7.9% BMI 28 kg/m2 6.3% So we’ve produced probability models for combining predictors of MODY but how can we use these in clinical practice? Well if we take an example of a patient This patient is insulin treated from diagnosis. Based on this information alone, we estimate their probability of MODY to be 0.7%. They are female, diagnosed aged 19, now 30. They have a parent with diabetes, an hba1c of 7.9% and a BMI of 28. If we add these characteristics to the clinical prediction model we get a probability of MODY of 6.3%. If however, we then found out they were negative for C-peptide, so not producing their own insulin, the probability of them having MODY would then go down to 1%. If on top of this, we found out they were positive for GAD antibodies then their probability would go down to 0.01%, so a 1 in 10,000 chance. C-peptide negative 1.0% GAD positive 0.01%

Example in practice Insulin treated from diagnosis 0.7% Female Probability of MODY Insulin treated from diagnosis 0.7% Female Diagnosed age 19, now 30 Parent with diabetes HbA1c 7.9% BMI 28 kg/m2 6.3% C-peptide negative positive 1.0% 15.6% GAD positive GAD/IA2 negative 0.01% 51.5%

How do you refer a patient for genetic testing ? Download a ‘Diagnostic request form’ from www.diabetesgenes.org Complete form and send with EDTA sample to Exeter Discuss case if unsure (with myself) Costs apply for genetic testing (except neonatal diabetes) but agreed by UKGTN as appropriate for all meeting criteria

Maturity-onset diabetes of the young (MODY): in the post genetic era 22% Glucokinase 66% Transcription factors <1% Insulin <1% SUR1 11% MODY x 2% HNF1B 61% HNF1A 4% HNF4A <1% IPF1 <1% CEL

Defining the gene helps diagnosis Clinical features Specific beta-cell defect Finding gene mutation Makes diagnosis Pathophysiology Treatment Response

66% Transcription factors In Maturity-Onset Diabetes of the Young (MODY) genetic subtype determines clinical picture and treatment response MODY 22% Glucokinase 66% Transcription factors <1% CEL <1% Insulin 11% MODY x 2% HNF1 61% HNF1 4% HNF4  <1% IPF1 <1% NeuroD1 Treatment not needed Insulin Low dose SUs Insulin ?too rare

Family tree Pancreatic antibodies ‘Negative’ UCPCR ‘Positive’ Talk through family tree and autosomal dominant inheritance UCPCR ‘Positive’

When to consider monogenic diabetes Anyone diagnosed <25 years with an affected parent : Autosomal dominant inheritance, Young age of onset (<25 yrs), Non insulin dependent diabetes Anyone diagnosed ‘young’ with other features associated with monogenic diabetes e.g. mild stable hyperglycaemia, HbA1c 40-60mmol/mol (GCK) macrosomia, neonatal hypoglycaemia (HNF4A) low renal threshold for glucose, SU sensitivity, early MI (HNF1A) diabetes and deafness, maternal inheritance (MIDD) diabetes and renal cysts, single kidney, bicornate uterus (HNF1B) Anyone diagnosed <6 months of age (neonatal diabetes)

Monogenic Diabetes Symposium on 8-9th Feb 2017 For more information about monogenic diabetes please visit our website: www.diabetesgenes.org If you would like to learn more please register for our Monogenic Diabetes Symposium on 8-9th Feb 2017 agnieszka.graja@dchft.nhs.uk