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