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Publications about genetic testing for metabolic disorders
  1. MODY

MODY

January 15, 2019

Disease summary:

Maturity-onset diabetes of the young (MODY) is a clinically heterogeneous group of single-gene disorders.1,2 MODY is characterized by early onset of nonketotic diabetes mellitus caused by defective insulin production from the pancreatic beta-cells; it follows an autosomal dominant mode of inheritance. Patients can present with mild fasting hyperglycemia for many years, whereas others have varying degrees of glucose intolerance for several years before the onset of persistent fasting hyperglycemia.1 Because of its frequently mild presentation, it is one of the most easily missed causes of diabetes.3

MODY subtype, clinical phenotype and the most effective treatment options will differ depending on the defective gene and molecular characterization of the pathogenic variant is important.1,4


Autosomal dominant

  • >100/1,000,000. The prevalence of MODY in racial and ethnic minorities may be underrepresented as many individuals with MODY remain undiagnosed and studies to date have largely involved white populations.3
  • MODY is thought to account for at least 1%-3% of all diabetes.3,4
  • Early-onset (<25 years) diabetes
  • Non-insulin dependent diabetes
  • Can be mild, often asymptomatic
  • Mild fasting hypoglycemia
  • Glucose intolerance
  • Classic diabetes symptoms such as Polyuria, Polydipsia and polyphagia
  • Increased blood pressure >135/80 mm Hg
  • Abdominal pain (especially for variants in CEL gene)
  • The characteristic features of type 1 diabetes (severe osmotic symptoms, ketoacidosis) or type 2 diabetes (obesity, acanthosis nigrans, hypertension, hyperlipidemia) are typically absent in the patient with MODY.

5 major diagnostic criteria for MODY are usually accepted:5

  • Hyperglycemia usually diagnosed before age 25 years in at least 1 and ideally 2 family members.
  • Autosomal dominant inheritance, with a vertical transmission of diabetes through at least 3 generations, and a similar phenotype shared by diabetic family members.
  • Absence of insulin therapy at least 5 years after diagnosis or significant C-peptide levels even in a patient on insulin treatment.
  • Insulin levels that are often in the normal range, although inappropriately low for the degree of hyperglycemia, suggesting a primary defect in beta-cell function.
  • Overweight or obesity is rarely associated (and is not required for the development of diabetes).
  • Pancreatic islet cell autoantibody testing can be helpful in distinguishing between MODY and type 1 diabetes.6
  • Maintained levels of C-peptide would be anticipated in MODY.7
  • Molecular genetic testing to defined MODY subtype and causative gene and pathogenic variant.

MODY subtype identified by phenotype and/or molecular genetic characterization can influence treatment choices and efficacy.1,4

  • Oral hypoglycemic agent, insulin (MODY 1,3,4)
  • Insulin therapy (ABCC8, GCK, HNF1A, HNF1B, HNF4A)
  • Sulfonylureas (ABCC8, HNF1A, HNF1B, HNF4A, KCNJ11)
  • Diet and exercise (ABCC8, CEL, GCK, HNF1A, HNF1B, HNF4A, KLF11).
  • Type 2 diabetes mellitus
  • Type 1 diabetes mellitus

To confirm/establish the diagnosis of MODY, CENTOGENE offers the following tests:

  • NGS Panel
  • NGS Panel Genomic
  • Deletion/Duplication testing (MLPA/qPCR)
  • Individuals with a family history of disease and presentation of the most common symptoms.
  • Individuals without a positive family history, but with symptoms resembling this disease.
  • Individuals with a negative but suspected family history to identify risk and to allow proper genetic counselling.

MODY is initially misdiagnosed in 90% of cases, resulting in inappropriate advice and treatment. Confirmation by molecular genetic testing of the MODY subtype is important, as it enables correct diagnosis enabling treatment optimization and allowing monitoring of asymptomatic family members.8


Gene OMIM (Gene) Associated diseases (OMIM) Inheritance CentoMD® exclusive variant numbers (++)
ABCA1 600046 Tangier disease; HDL deficiency, type 2 AR 19
ABCC8 600509 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; leucine-sensitive hypoglycemia of infancy; familial hyperinsulinemic hypoglycemia type 1; transient neonatal diabetes mellitus type 2 AD, AR 33
ACAT1 607809 alpha-methylacetoacetic aciduria AR 11
ACSF3 614245 Combined malonic and methylmalonic aciduria 16
AFF4 604417 CHOPS syndrome AD 2
AGL 610860 glycogen storage disease type III AR 86
AKT2 164731 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hypoinsulinemic hypoglycemia with hemihypertrophy AD 2
ALDOA 103850 Glycogen storage disease XII AR 8
ALDOB 612724 hereditary fructose intolerance AR 7
ALG1 605907 congenital disorder of glycosylation type 1k AR 5
ALG11 613666 congenital disorder of glycosylation type 1p AR 6
ALG12 607144 congenital disorder of glycosylation type 1g AR 1
ALG13 300776 congenital disorder of glycosylation type 1s XLD 6
ALG2 607905 congenital disorder of glycosylation type 1i AR 2
ALG3 608750 congenital disorder of glycosylation type 1d AR 4
ALG6 604566 congenital disorder of glycosylation type 1c AR 1
ALG8 608103 congenital disorder of glycosylation type 1h AD, AR 2
ALG9 606941 Gillessen-Kaesbach-Nishimura syndrome; congenital disorder of glycosylation type 1l AR 0
APOA1 107680 Amyloidosis, familial visceral AD 0
APOA5 606368 HYPERLIPOPROTEINEMIA, TYPE V; Hypertriglyceridemia, susceptibility to AD 4
APOB 107730 Hypercholesterolemia, Type B; Hypobetalipoproteinemia AD, AR 64
APOC2 608083 Apolipoprotein C-Ii Deficiency AR 5
APOE 107741 Alzheimer Disease 2; Sea-blue histiocyte disease; Macular Degeneration, Age-Related, 1; early-onset familial Alzheimer disease-3; Lipoprotein glomerulopathy AD, AR 10
ARL13B 608922 Joubert syndrome 8 AR 2
ARL6 608845 Bardet-Biedl syndrome type 1; Bardet-Biedl syndrome 3; Retinitis pigmentosa 55 AR, DiR 6
ATP6V0A2 611716 autosomal recessive cutis laxa type IIA; Wrinkly skin syndrome AR 1
B4GALT1 137060 congenital disorder of glycosylation type 2d AR 2
BBS1 209901 Bardet-Biedl syndrome type 1 AR, DiR 14
BBS10 610148 Bardet-Biedl syndrome type 10 AR 11
BBS12 610683 Bardet-Biedl syndrome type 12 AR 8
BBS2 606151 Bardet-Biedl syndrome type 2; retinitis pigmentosa type 74 AR 16
BBS4 600374 Bardet-Biedl syndrome 4 AR 11
BBS5 603650 Bardet-Biedl syndrome 5 AR 27
BBS7 607590 Bardet-Biedl syndrome type 7 AR 17
BBS9 607968 Bardet-Biedl syndrome type 9 AR 24
BDNF 113505 2
BLK 191305 MODY type 11 AD 15
C8orf37 614477 Cone-rod dystrophy 16; Bardet-Biedl syndrome type 21 AR 3
CC2D2A 612013 COACH syndrome; Meckel syndrome 6; Joubert syndrome 9 AR 24
CCDC28B 610162 Bardet-Biedl syndrome type 1 AR, DiR 1
CEL 114840 MODY type 8 AD 38
CEP164 614848 nephronophthisis 15 AR 14
CEP290 610142 Joubert syndrome type 5; Senior-Loken syndrome type 6; Meckel syndrome type 4; Leber congenital amaurosis type 10; Bardet-Biedl syndrome type 14 AR 51
CHD2 602119 childhood-onset epileptic encephalopathy AD 11
CISD2 611507 Wolfram syndrome 2 AR 14
COG1 606973 Congenital disorder of glycosylation, type IIg AR 1
COG4 606976 congenital disorder of glycosylation type 2j; Saul-Wilson syndrome AD, AR 4
COG5 606821 Congenital disorder of glycosylation, type IIi AR 0
COG6 606977 congenital disorder of glycosylation type 2l; Shaheen syndrome AR 4
COG7 606978 Congenital disorder of glycosylation, type IIe AR 3
COG8 606979 congenital disorder of glycosylation type 2h 1
CP 117700 aceruloplasminemia AR 17
CREBBP 600140 Rubinstein-Taybi syndrome 1 AD 39
CUL4B 300304 MENTAL RETARDATION, X-LINKED 15 XLR 8
CYP27A1 606530 cerebrotendinous xanthomatosis AR 6
DDOST 602202 Congenital disorder of glycosylation, type Ir AR 1
DHDDS 608172 retinitis pigmentosa type 59; Developmental delay and seizures with or without movement abnormalities AD, AR 2
DOLK 610746 congenital disorder of glycosylation type 1m AR 2
DPM1 603503 Congenital disorder of glycosylation, type Ie AR 1
DPM2 603564 Congenital disorder of glycosylation, type Iu AR 0
DPM3 605951 congenital disorder of glycosylation, type Io AR 1
DYRK1B 604556 Abdominal obesity-metabolic syndrome 3 AD 0
EIF2AK3 604032 Wolcott-Rallison syndrome AR 2
ENO3 131370 Glycogen storage disease XIII AR 13
ENPP1 173335 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Arterial calcification, generalized, of infancy, 1; OBESITY; Hypophosphatemic rickets, autosomal recessive, 2; Cole disease AD, AR 8
EPM2A 607566 Epilepsy, progressive myoclonic 2A (Lafora); Epilepsy, progressive myoclonic 2B (Lafora) AR 5
FBP1 611570 Fructose-1,6-bidphosphatase deficiency AR 14
FOXP3 300292 Immunodysregulation, polyendocrinopathy, and enteropathy, X-linked XLR 5
G6PC 613742 glycogen storage disease type IA AR 16
GAA 606800 Pompe disease AR 130
GATA6 601656 Tetralogy of Fallot; Conotruncal Heart Malformations; Pancreatic agenesis and congenital heart defects; Atrioventricular septal defect 5; Atrial septal defect 9 AD 2
GBE1 607839 storage disease type 4; Polyglucosan body disease, adult form AR 40
GCK 138079 MODY type 2; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Hyperinsulinemic hypoglycemia, familial, 3; permanent neonatal diabetes mellitus AD, AR 30
GHR 600946 familial hypercholesterolemia; Laron syndrome; Increased responsiveness to growth hormone AD, AR 11
GLI3 165240 Pallister-Hall syndrome; Polydactyly, postaxial, types A1 and B; Preaxial polydactyly type IV; Greig cephalopolysyndactyly syndrome AD 30
GLIS3 610192 Diabetes mellitus, neonatal, with congenital hypothyroidism AR 6
GLUD1 138130 familial hyperinsulinemic hypoglycemia-6 AD 5
GMPPA 615495 Alacrima, achalasia, and mental retardation syndrome AR 2
GNAS 139320 Pseudohypoparathyroidism Ia; Osseous heteroplasia, progressive; McCune-Albright syndrome, somatic, mosaic; ACTH-independent macronodular adrenal hyperplasia; Pseudohypoparathyroidism type Ib; Pseudohypoparathyroidism Ic; Pseudopseudohypoparathyroidism AD 23
GNE 603824 Sialuria; Nonaka myopathy AD, AR 6
GPIHBP1 612757 Hyperlipoproteinemia, type 1D AR 2
GYG1 603942 Glycogen storage disease XV; Polyglucosan body myopathy 2 AR 11
GYS1 138570 Glycogen storage disease 0, muscle AR 8
GYS2 138571 Glycogen storage disease 0, liver AR 24
HADH 601609 3-hydroxyacyl-CoA dehydrogenase deficiency; familial hyperinsulinemic hypoglycemia type 4 AR 0
HEXA 606869 Tay-Sachs disease/ GM2-gangliosidosis AR 25
HMGCL 613898 HMG-CoA lyase deficiency AR 10
HMGCS2 600234 HMG-CoA synthase-2 deficiency AR 4
HNF1A 142410 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Renal carcinoma, chromophobe, somatic; Diabetes mellitus, insulin-dependent-1; MODY type 3 AD, AR 20
HNF1B 189907 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 5; Renal carcinoma, chromophobe, somatic AD 14
HNF4A 600281 MODY type 1; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi renotubular syndrome 4, with maturity-onset diabetes of the young AD 11
IER3IP1 609382 Microcephaly, epilepsy, and diabetes syndrome AR 1
IFT172 607386 Short-rib thoracic dysplasia 10 with or without polydactyly AR 4
IFT27 615870 Bardet-Biedl syndrome 19 AR 0
INPP5E 613037 Joubert syndrome 1; Mental retardation, truncal obesity, retinal dystrophy, and micropenis AR 18
INS 176730 Diabetes Mellitus, Insulin-Dependent, 2; MODY type 10 AD, AR 5
INSR 147670 Donohue syndrome; Rabson-Mendenhall syndrome; Hyperinsulinemic hypoglycemia, familial, 5; Diabetes mellitus, insulin-resistant, with acanthosis nigricans AD, AR 34
KCNJ11 600937 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; familial hyperinsulinemic hypoglycemia type 2; transient neonatal diabetes mellitus type 3; MODY type 13 AD, AR 7
KIF7 611254 Acrocallosal syndrome; Joubert syndrome 12; Hydrolethalus syndrome 2 AR 25
KLF11 603301 MODY type 7 12
LAMP2 309060 Danon disease XLD 12
LARGE1 603590 congenital muscular dystrophy-dystroglycanopathy with mental retardation type B6; congenital muscular dystrophy-dystroglycanopathy with brain and eye anomalies type A6 AR 19
LDHA 150000 Glycogen storage disease XI AR 5
LDLR 606945 familial hypercholesterolemia AD 11
LDLRAP1 605747 Hypercholesterolemia, Autosomal Recessive AR 2
LEP 164160 Leptin deficiency AR 3
LEPR 601007 Morbid obesity due to leptin receptor deficiency AR 1
LIPA 613497 Wolman disease / cholesteryl ester storage disease AR 21
LIPE 151750 Lipodystrophy, familial partial, type 6 AR 0
LPL 609708 familial combined hyperlipidemia; lipoprotein lipase deficiency AD, AR 14
LZTFL1 606568 Bardet-Biedl syndrome 17 AR 5
MAGEL2 605283 Schaaf-Yang syndrome AD 9
MAN1B1 604346 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 15 AR 2
MC4R 155541 AD, AR 0
MGAT2 602616 Congenital disorder of glycosylation, type IIa AR 4
MKKS 604896 McKusick-Kaufman syndrome; Bardet-Biedl syndrome type 6 AR 6
MKS1 609883 Meckel syndrome type 1; Bardet-Biedl syndrome type 13; Joubert syndrome type 28 AR 7
MOGS 601336 congenital disorder of glycosylation type 2b AR 5
MPDU1 604041 congenital disorder of glycosylation type 1f AR 1
MPI 154550 congenital disorder of glycosylation type 1b AR 1
MPV17 137960 mitochondrial DNA depletion syndrome type 6 AR 7
MTTP 157147 Abetalipoproteinemia; protection against metabolic syndrome AD, AR 1
MYO5A 160777 Griscelli syndrome, type 1 AR 31
MYO7A 276903 Usher syndrome type 1B; deafness type 2; autosomal dominant deafness type 11 AD, AR 31
NDN 602117 Prader-Willi syndrome AD 2
NEUROD1 601724 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; MODY type 6 AD 3
NEUROG3 604882 Diarrhea 4, malabsorptive, congenital AR 2
NGLY1 610661 Congenital disorder of deglycosylation AR 11
NHLRC1 608072 Epilepsy, progressive myoclonic 2A (Lafora); Epilepsy, progressive myoclonic 2B (Lafora) AR 3
NPHP1 607100 nephronophthisis 1; Joubert syndrome 4 AR 19
NPHP3 608002 Renal-hepatic-pancreatic dysplasia 1; Meckel syndrome 7; nephronophthisis 3 AR 16
NR0B2 604630 OBESITY AD, AR 0
NTRK2 600456 Obesity, hyperphagia, and developmental delay; early infantile epileptic encephalopathy type 58 AD 3
OFD1 300170 Simpson-Golabi-Behmel syndrome type 2; Retinitis pigmentosa 23; Joubert syndrome 10; oral-facial-digital syndrome 1 XLD, XLR 22
OXCT1 601424 Succinyl CoA:3-oxoacid CoA transferase deficiency AR 5
PAX4 167413 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Maturity-onset diabetes of the young, type IX AD, AR 11
PC 608786 pyruvate carboxylase deficiency AR 13
PCK1 614168 Phosphoenolpyruvate carboxykinase-1, cytosolic, deficiency AR 3
PCNT 605925 microcephalic osteodysplastic primordial dwarfism type 2 AR 42
PCSK1 162150 Obesity with impaired prohormone processing AR 2
PCSK9 607786 hypercholesterolemia-3 AD 4
PDX1 600733 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Pancreatic Agenesis, Congenital; MODY type 4 AD, AR 10
PFKM 610681 Glycogen storage disease type VII AR 17
PGAM2 612931 Glycogen storage disease X AR 6
PGK1 311800 Phosphoglycerate kinase 1 deficiency XLR 6
PGM1 171900 congenital disorder of glycosylation type 1t AR 23
PHF6 300414 Borjeson-Forssman-Lehmann syndrome XLR 5
PHKA1 311870 Muscle glycogenosis XLR 15
PHKA2 300798 glycogen storage disease type IX XLR 40
PHKB 172490 Glycogen storage disease IXb; Phosphorylase kinase deficiency of liver and muscle AR 30
PHKG2 172471 Glycogen storage disease IXc AR 14
PMM2 601785 congenital disorder of glycosylation type 1a AR 3
PNPLA6 603197 Boucher-Neuhauser syndrome; spastic paraplegia 39 AR 55
POMC 176830 OBESITY; Proopiomelanocortin Deficiency AD, AR 2
PPARG 601487 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; OBESITY; Lipodystrophy, familial partial, type 3 AD, AR 2
PRKAG2 602743 Wolff-Parkinson-White syndrome; fatal congenital hypertrophic cardiomyopathy due to glycogen storage disease; familial hypertrophic cardiomyopathy 6 AD 19
PROM1 604365 Stargardt disease 4; Macular dystrophy, retinal, 2; Retinitis pigmentosa 41; Cone-rod dystrophy 12 AD, AR 27
PRPH2 179605 Retinitis punctata albescens; Patterned dystrophy of retinal pigment epithelium (macular dystrophy); Retinitis pigmentosa 7; vitelliform macular dystrophy-3; Choriodal dystrophy, central areolar 2 AD, AR 7
PTF1A 607194 Pancreatic Agenesis 2 AR 3
PYGL 613741 glycogen storage disease type 6 AR 36
PYGM 608455 glycogen storage disease type 5 AR 37
RAB23 606144 Carpenter syndrome AR 0
RAI1 607642 Smith-Magenis syndrome AD 12
RBCK1 610924 Polyglucosan body myopathy 1 with or without immunodeficiency AR 7
RDH5 601617 Retinitis punctata albescens AD, AR 1
RFT1 611908 congenital disorder of glycosylation type 1n AR 3
RFX6 612659 Mitchell-Riley syndrome AR 30
RHO 180380 Retinitis punctata albescens; Night blindness, congenital stationary, autosomal dominant 1; Retinitis Pigmentosa 4 AD, AR 1
RLBP1 180090 Retinitis punctata albescens AD, AR 4
RPGRIP1L 610937 COACH syndrome; Joubert syndrome 7; Meckel syndrome type 5 AR 18
RPS6KA3 300075 MENTAL RETARDATION, X-LINKED 19; Coffin-Lowry syndrome XLD 17
SDCCAG8 613524 Senior-Loken syndrome 7; Bardet-Biedl syndrome 16 AR 12
SIM1 603128 2
SLC16A1 600682 Monocarboxylate transporter 1 deficiency AD, AR 4
SLC19A2 603941 Thiamine-responsive megaloblastic anemia syndrome AR 1
SLC2A2 138160 noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Fanconi-Bickel syndrome AD, AR 31
SLC35A1 605634 Congenital disorder of glycosylation, type IIf AR 0
SLC35A2 314375 congenital disorder of glycosylation type 2m XLD 3
SLC35C1 605881 Congenital disorder of glycosylation, type IIc AR 1
SPG11 610844 Amyotrophic lateral sclerosis 5, juvenile; spastic paraplegia type 11; Charcot-Marie-Tooth disease, axonal, type 2X AR 72
SRD5A3 611715 congenital disorder of glycosylation type 1q; Kahrizi syndrome AR 1
SSR4 300090 congenital disorder of glycosylation type 1y XLR 1
STT3A 601134 congenital disorder of glycosylation type 1w AR 2
STT3B 608605 Congenital disorder of glycosylation, type Ix AR 0
TMEM165 614726 Congenital disorder of glycosylation, type IIk AR 0
TMEM67 609884 COACH syndrome; Meckel Syndrome, Type 3; Joubert syndrome 6; nephronophthisis 11; Bardet-Biedl syndrome type 14 AR 22
TRIM32 602290 limb-girdle muscular dystrophy type 2H; Bardet-Biedl syndrome 11 AR 2
TTC21B 612014 Short-rib thoracic dysplasia 4 with or without polydactyly; nephronophthisis 12 AD, AR 24
TTC8 608132 retinitis pigmentosa type 51; Bardet-Biedl syndrome type 8 AR 13
TUSC3 601385 MENTAL RETARDATION, AUTOSOMAL RECESSIVE 7 AR 1
UCP2 601693 0
UCP3 602044 OBESITY AD, AR 0
VPS13B 607817 Cohen syndrome AR 28
WDPCP 613580 Bardet-Biedl syndrome 15 AR 9
WFS1 606201 congenital nuclear cataract type 41; noninsulin-dependent diabetes mellitus / Diabetes mellitus type II; Wolfram syndrome; Deafness, autosomal dominant 6/14/38; Wolfram-like syndrome AD, AR 22
ZFP57 612192 Diabetes mellitus, transient neonatal, 1 AD 7