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Title - Next Generation Sequencing based comprehensive

molecular studies in young onset diabetes

Author / Presenter : Aaron Chapla, Deny Varghese, Manika Varshney

Asha HS,Deepak Abraham*, Thomas V Paul, Nihal Thomas.

Institute: Departments Of Endocrinology1, Endocrine Surgery*, Christian Medical College, Vellore, India.

BACKGROUND: T2DM pathophysiology which is characterized by insulin resistance and relative impairment in insulin secretion can be explained in individuals whose BMI is above 25 Kg/m2. In T2D, β cells via the feedback loop compensate to the increasing need of insulin and maintain a fine balance with the insulin sensitive tissues to sustain normoglycemia and the onset of T2D is usually above 35 years.

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METHODS

NEXT GENERATION SEQUENCING

BASED METHODOLOGY

STRATIFICATION OF STUDY SUBJECTS

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MEPN

Sex

Age

AOD

BMI

TREATMENT

GENE

MODY

Mutation

Aminoacid change

M85

F

37

27

21.7

Insulin

HNF4A*

MODY1

c.811G>A

p.Glu271Lys

M10

M

23

21

25

Metformin

HNF4A

MODY

c.505G>A c.493-4G>A (splice site mutation) c.493-20C>T

p.Val169Ile

BLK

c.953G>A

p.G318E

M15

F

8

8

 

Diet

GCK

MODY2

c.1318G>T

p.Glu440X

M01

F

21

11

19.1

Insulin & Glibenclamide

HNF1A

MODY

c.1501G>T

p.Ala501Ser

ABCC8

c.1555G>A

p.R519C

M62

M

40

26

24.4

Insulin

PDX1

MODY4

c.529G>A

p.Val177Met

M19

F

27

25

26.3

Metformin & Insulin

HNF1B

MODY5

c.274C>T

p.Leu92Phe

M26

M

47

28

22.8

Glimepiride

NEUROD1

MODY

c.723C>G

p.His241Gln

PDX1

c.670G>A

p.Glu224Lys

M47

F

35

24

39.7

Metformin & Glimepride

NEUROD1

MODY6

c.723C>G

p.His241Gln

M18

M

30

30

19.3

Glimepiride

NEUROD1

MODY6

c.175 G>C

p.Glu59Gln

M30

M

30

30

27.5

Metformin & Glipizide

NEUROD1

MODY

c.-162G>A 5'UTR

 

PDX1

c.670G>A

p.Glu224Lys

M33

M

14

14

23

Glimepiride & Insulin

PAX4

MODY

c.92G>T

p.Arg31Leu

ABCC8

c.487C>T

p.G163S

M05

F

28

52

32

Metformin & Glimepride 

ABCC8

MODY12 

c.487C>T

p.G163S

M12

F

26

29

 

Insulin  

ABCC8

MODY12

c.1005C>A

p.Q335H

M32

F

14

14

30

Metformin 

ABCC8

MODY12

c.3995G>A

p.S1332L

M43

F

27

30

27

 Metformin

ABCC8

MODY ?  

c.2209C>T

p.V737I

M29

M

24

40

28

Metformin & Glimepride 

KCNJ11

MODY13 

c.247A>G

p.W83R

MUTATIONS IDENTIFIED UTILIZING THE 2GDMODY PROTOCOL

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Summary of mutations in MODY subjects

N=15

N=41

N=1

N=23

N=6

BMI-22.7±2.9

N=12

N=4

BMI-27.6±5

BMI-22.7±2.9

Group I- N =56

Clinically suspected MODY

Group II- N =24

Young onset diabetes

N=9

N=6

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  • Through this study NGS based cost-effective, scalable, accurate molecular method was established for comprehensive parallelized genetic testing in clinical settings
  • We have identified 27% mutation positive rate in subjects with suspected MODY and 4% mutation positive rate in subjects with young onset diabetes when screened for a complete panel of all the known 13 MODY genes.
  • First report of PDX1, HNF1Β, PAX4, KLF11, BLK11 novel mutations from India and also first report of novel digenic NEUROD1+PDX1, PAX4+ABCC8, HNF4A+ABCC8 mutations.
  • The subjects with digenic mutations (6/15) had a mean BMI of 22.7kg/m2 and those subjects with single gene mutation had a BMI of 28kg/m2 . This data suggest that subjects with higher mutational burden could be predisposed to develop diabetes even with low BMI.

Summary and conclusions of the study

Reference: Aaron Chapla, Mahesh Doddabelavangala Mruthyunjaya, Hesarghatta Shyamasunder Asha, Denny Varghese, Manika Varshney, Senthil K Vasan,

Padmanaban Venkatesan, Veena Nair, Sarah Mathai, Thomas Vizhalil Paul and Nihal Thomas. Maturity onset diabetes of the young in india.-a distinctive mutation

pattern identified through targeted next generation sequencing. Clinical Endocrinology, Volume 82, Issue 4, April 2015 Pages 533–542.

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