6. Complex genetic disorders

Question 1

Diabetes

Answer 1

chronic hyperglycaemic state
characterised by beta cell dysfunction and/or insulin resistance
polygenic or monogenic

Question 2

Type 1 Diabetes

Answer 2

Autoimmune system destroys pancreatic beta cells
Diminished/absent endogenous beta cell function, no/ little production of insulin
Presents at any age

Question 3

Treatment of Type 1 diabetes

Answer 3

Insulin replacement

Question 4

Type 2 Diabetes

Answer 4

resistance to insulin action leads to increased production and ultimately pancreatic exhaustion
Presents at middle/old age, increasing in youth

Question 5

Treatment of type 2 diabetes

Answer 5

Diet
Exercise
Oral hypoglycaemic agents
Eventually insulin

Question 6

Monogenic diabetes

Answer 6

Single gene defect:
Maturity onset diabetes of the young (MODY)
Permanent neonatal diabetes (PND)

Question 7

Maturity onset diabetes of the young (MODY)

Answer 7

Collection of autosomal dominant monogenic disorders affecting genes involved in beta-cell glucose sensing and insulin secretion.
Often mutation of HNF1-α or Glucokinase
Different from Type 1 & Type 2 diabetes

Question 8

Heritability

Answer 8

Study of genetic contribution to increased risk of a disease

Difficult to disentangle genetic from non-genetic factors

Question 9

Percentage of diabetes that is monogenic and polygenic

Answer 9

monogenic: 5%, born with it
polygenic: 95%, may develop it

Question 10

Proportion of T1DM and T2DM that are polygenic

Answer 10

T1DM: 5%
T2DM: 95%

Question 11

Monogenic diabetes

Answer 11

100% risk of developing diabetes
No environmental factors
100% heritable

Question 12

Polygenic diabetes

Answer 12

T1/2
Not born with it but can have genetic predisposition
Compilation of genetic changes that increase predisposition
Not 100% risk
Affected by environment

Question 13

What is the difference between monogenic and polygenic diabetes?

Answer 13

In polygenic there has to be a 2nd hit to develop diabetes:
Environmental
Lifestyle

Question 14

What are genome wide association studies (GWAS)?

Answer 14

Hypothesis free approach to find common variants in common disease
Looking to identify SNPs statistically associated with disease

Question 15

Genomic Copy Number Variation (CNVs)

Answer 15

Deletions/duplications/insertions in genome
Range from few base pairs to > 1Mb
Can increase risk of polygenic disease
Common in obesity
Most risk appears to be conferred through single nucleotide changes

Question 16

What did GWAS show for Type 2 diabetes?

Answer 16

SNPs account for 6%

Shows environment is heavily influential

Question 17

What is Hepatic nuclear factor 1-alpha (HNF1-alpha)?

Answer 17

Transcription factor that stimulates insulin production

Question 18

What is the consequence of absence/ mutation of HNF-1 alpha?

Answer 18

Insulin production reduced

Only manifests in adulthood when beta- cell function starts to naturally decline

Question 19

How are HNF1-alpha mutations best managed?

Answer 19

With sulphonylureas

Question 20

What are those with HNF1-alpha mutations at risk of?

Answer 20

Micro- and microvascular complications

Question 21

Clinical features of HNF1-alpha mutations

Answer 21

Hypoglycaemic response to low dose sulphonylureas
Young onset
Generational family history
Non- insulin requiring
Atypical for T1/T2

Question 22

What is glucokinase?

Answer 22

Enzyme that converts glucose to glucose-6-phosphate

Triggered at certain beta-cell glucose levels

Question 23

What do glucokinase mutations result in?

Answer 23

Higher set-point at which insulin secretion is triggered

Question 24

What defect characterises MODY 2?

Answer 24

Glucokinase mutation

Question 25

Features of MODY 2

Answer 25

High fasting and low post-prandial plasma glucose Stable, mild hyperglycaemia Often misdiagnosed as T2DM, IFG or GDM

Question 26

Why are there not often complications to MODY 2?

Answer 26

Isolated risk factor Hyperglycaemia is mild and under homeostatic regulation Similar insulin resistance and obesity as general population ‘Normal’ lipid profile

Question 27

Name 2 rarer types of HNF mutation

Answer 27

HNF-4 alpha | HNF-1 beta

Question 28

Describe HNF-4 alpha mutation

Answer 28

``` Clinically similar to HNF-1 alpha but rarer Older age of onset Low renal glucose threshold Macrosomia Transient neonatal hypoglycaemia ```

Question 29

What characterises HNF-1 beta mutation (RCAD)?

Answer 29

Renal cysts and diabetes | Genital tract mutations

Question 30

What are the barriers to diagnosing monogenic diabetes?

Answer 30

Incomplete understanding regarding benefits of diagnosis Clinical challenge: need to think of it to make diagnosis Access to genetic testing and robust interpretation Interpreting variants of unknown significance Needle in haystack

Question 31

Mitochondrial diabetes

Answer 31

Maternally inherited diabetes and deafness (MIDD) | Associated with MELAS

Question 32

Features of MIDD

Answer 32

``` Diabetes Young-onset sensorineural deafness Lactate Muscle aches Short stature ```

Question 33

Permanent neonatal diabetes features

Answer 33

Monogenic Diabetes in 1st 6 months of life Genetic defect resulting from mutations in KCNJ11, ABCC8 and INS

Question 34

Precision diabetes allows accurate diagnosis and treatment

Answer 34

SNPs predict metformin side effects | Use sulphonylureas in HNF1a MODY and PND