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GeNeViSTA
Subset | Syndromes
|
Chromosomal disorders | Down syndrome, Klinefelter syndrome, Turner syndrome |
Triplet Repeat Disorders | Huntington disease, Friedreich ataxia, Myotonic dystrophy |
Obesity associated syndromes | Bardet-Biedel syndrome, Prader-Willi syndrome, Alstrom syndrome |
Others | Wolfram syndrome |
NDM can be classified into transient (TNDM) and permanent forms. Approximately 50% of cases are transient in nature and the diabetes resolves on its own. The most common cause for TNDM is overexpression of the chromosome region 6q24. Although hyperglycaemia remits in TNDM patients by the age of 18 months, a relapse of diabetes occurs in 50% of the patients, usually during adolescence or early adulthood (Mackay & Temple, 2010). On the other hand, permanent NDM most often results from gain of function mutations in KCNJ11 or ABCC8 gene. These can be successfully treated with high doses of sulfonylureas unlike other NDM which require treatment with insulin. The most common genes and associated features involved in NDM are described in Table 2.
NDM | Genetic cause | Mode of | Pathogenesis | Associated | Treatment |
|
| inheritance |
| features |
|
||
Overexpression of chromosome 6q24 • Paternal UPD • Paternal duplication • Maternal hypomethylation | • AD | Overexpression of ZAC1 and HYMA1 on chromosome 6 causes delayed maturation of the pancreatic islets and β-cells | IUGR, Cardiac abnormalities | Insulin |
||
Transient | KCNJ11, ABCC8 (KCNJ11 encodes KATP channel subunits KIR6.2, ABCC8 encodes Sulfonylurea receptor) | Sporadic /AD | Mutation results in prolonged opening of potassium channel and hampering of insulin release | None | Insulin Sulfonylureas |
|
HNF-1B * | AD | Reduced pancreatic β cell mass | Pancreatic exocrine dysfunction, renal cysts/ hyperechoic kidneys | Insulin |
||
Permanent |
Non syndromic | KCNJ11, ABCC8 | Sporadic /AD | Same as above | Developmental delay, epilepsy (DEND syndrome) | Insulin Sulfonylureas |
INS | AD | Pancreatic β-cell apoptosis | IUGR | Insulin |
||
GCK # | AR | Affects glucose phosphorylation and blocks ATP production; causes reduction of insulin secretion | IUGR | Insulin |
||
IPF1 | AR | Marked pancreatic exocrine and endocrine failure due to pancreatic agenesis | Cerebellar hypoplasia, cardiac septal defects | Insulin |
||
Syndromic | EIF2AK3 | AR | Pancreatic β-cell apoptosis | Wolcott- Rallison syndrome | Insulin |
|
FOXP3 | X linked | Pancreatic β-cell apoptosis | IPEX syndrome | Insulin |
||
SLC2A2 | AR | Reduced pancreatic β-cell function | Fanconi- Bickel syndrome | Insulin |
||
SLC19A2 | AR | Reduced pancreatic β-cell function | TRMA syndrome | Insulin (Thiamine rarely) |
||
MTLL1 | Mitochondrial | Reduced pancreatic β-cell function | MIDD syndrome | Insulin |
||
NDM: Neonatal diabetes mellitus; UPD: Uniparental disomy; AD: Autosomal Dominant; AR: Autosomal Recessive; ZAC-1: zinc finger, apoptosis, and cell cycle; HYMA1: ([Fe] hydrogenase subunit HymA); IUGR: Intrauterine growth restriction; INS: Insulin; GCK: Glucokinase; IPF1: Insulin promoter factor 1; EIF2AK3: Eukaryotic translation initiation factor; IPEX- Immuno dysregulation, polyendocrinopathy, enteropathy, X-linked; TRMA: Thiamine-responsive megaloblastic anemia; MIDD- Maternally inherited diabetes and deafness. *Also implicated in MODY-4, #Also implicated in MODY-2
They are less common than monogenic β-cell defects. They typically present with features of insulin resistance in the absence of obesity, including hyperinsulinemia, acanthosis nigricans or virilization. Diabetes only develops when the β-cells fail to compensate for the insulin resistance. The common genes and syndromes associated with insulin resistance are listed in Table 3.
Gene | Inheritance | Disease | Phenotype |
INSR | AR | Rabson-Mendenhall syndrome | Extreme
insulin
resistance,
dysmorphism,
severe |
INSR | AR | Leprechaunism (Donohue syndrome) |
|
INSR | AR | Type A insulin resistance | Milder form, manifestation after puberty |
LMNA |
AD |
Familial
partial
lipodystrophy | Limb
lipoatrophy
in
adult
life,
hyperlipidemia |
PPARG |
| Partial
lipodystrophy,
severe
insulin
resistance, |
|
AGPAT2 |
AR |
Congenital
generalized
lipodystrophy |
Lipoatrophy,
acanthosis
nigricans,
hepatomegaly,
acromegaloid
features, cardiomyopathy and global development delay. |
|
|
||
BSCL2 |
|
|
|
|
|
||
AD- Autosomal dominant, AR- Autosomal Recessive
Type 2 DM can remain undiagnosed and can be recognised initially during pregnancy. It is essential to distinguish between GDM and type 2 DM in pregnancy as the latter is associated with a higher incidence of fetal malformations like caudal regression syndrome, congenital heart defects, renal anomalies etc. Family history of GDM and type 2 DM can act as a guide to predict risk of GDM. Women diagnosed with GDM are also at a significant risk for developing type 2 DM later in life.
Identification of monogenic diabetes has very significant relevance in pregnancy. Hyperglycemia in pregnancy is invariably always labelled as GDM but some of these patients may harbour mutation in the GCK (glucokinase) gene and identification of these women is important as the management differs substantially. Glucose-lowering agents are generally not required in GCK-associated MODY in normal individuals as the hyperglycemia is usually subclinical. Pregnancy is an exception where the requirement of treatment for GCK-associated MODY in pregnant woman depends on fetal inheritance of the GCK mutation. If the fetus inherits a maternal GCK mutation, then treatment of maternal hyperglycemia is not indicated as these fetuses have a similarly elevated glucose set-point as their mother and can have normal birth weight. On the other hand, treatment of maternal hyperglycemia is required in those fetuses who do not inherit GCK mutation, as they have a higher risk of developing macrosomia. When the fetal genotype is unknown, it can be indirectly inferred from monitoring serial fetal growth and an accelerated fetal growth would indicate that the fetus is probably not carrying the GCK mutation, warranting strict control of maternal hyperglycemia (Rudland, 2019).
The common situation for counselling in genetic clinics pertaining to DM arises when a pregnant diabetic mother consults to know the impact of diabetes on her fetus. Apart from that situation, very rarely counseling is sought for family or personal history of DM. An exception to this situation arises when the diagnosis of DM is made in a young individual where family members are anxious about recurrence in the offspring and in the siblings of the affected child. Due to increasing incidence of the disease, increasing list of genes and susceptible loci and studies showing monogenic diabetes being misdiagnosed as type 1 or 2 DM (Pihoker et al., 2013), it is important to make an accurate and timely diagnosis for appropriate genetic counselling regarding the optimal therapy. Though the risk of recurrence is negligible in majority of cases, counselling in the rare types of autosomal recessive, X-linked and syndromic DM is vital as parents can opt for prenatal testing after establishing molecular diagnosis in the index patient.
The following points are pertinent:
The age of onset; Table 4 enumerates the age-wise distribution of different types of DM and a few key points to differentiate one type from the other.
Type of intervention required and response to those medications
Associated visual or hearing impairment
Birth history including birth weight and birth defects
Detailed development history
Three-generation family history
Age of onset | Type of DM | Others |
<6 months (sometimes up to 1 year) | Neonatal DM | Genetic testing to distinguish transient from permanent |
6 months – 10 years | Type 1 DM Neonatal DM | Thin individuals; positive autoantibodies confirm Type 1 DM |
10-25 years | Type 1 DM Type 2 DM Monogenic DM | Overweight
or
obesity;
acanthosis
nigricans;
strong
family
history Strong
family
history
suggesting
AD
pattern;
undetectable
islet
autoantibodies; |
25-50 years | Type 2 DM Slowly
evolving
immune
mediated
DM Type 1 DM (5%) |
Thin
individuals;
presence
of
autoantibodies
(especially
GAD); initial response to sulfonylureas and later requiring insulin suggests LADA. |
>50 years | Type 2 DM Slowly evolving immune mediated DM |
|
DM: Diabetes mellitus; GAD: glutamic acid decarboxylase; LADA: latent autoimmune diabetes of adulthood
While examining the patient, special attention should be given to look for presence of dysmorphic features, obesity, distribution of fat, signs of hyperinsulinemia and multisystem involvement like anemia, deafness, renal cyst and neurocognitive abnormalities. For example, Thiamine-responsive megaloblastic anemia (TRMA) is a rare disorder which may present with severe anemia responding to thiamine. Presence of macrocytosis and deafness may be a clue for this disorder. Diabetes may sometimes manifest later and may need evaluation.
After obtaining necessary information and baseline investigations like autoantibodies profile if available, one can ascertain the type of DM and can decide whether to proceed with genetic testing. Molecular testing is indicated in monogenic forms of diabetes. This should be followed by discussion regarding the risk of recurrence in subsequent pregnancies and options for prenatal testing.
For monogenic disorders, counseling regarding recurrence risk in autosomal recessive and X-linked disorders is quite straight forward once the molecular diagnosis is established. However, rare autosomal dominant disorders pose significant challenge in counselling as the genetic evidence on penetrance of these genes is weak (Misra & Owen, 2018). Counselling for the recurrence risks of Type 1 and type 2 DM on the other hand is complex. Empiric risks can be used based on the family history and the community prevalence of the disease but these have their own limitations.
Type 1 DM: Previous studies have reported that younger age at diagnosis, young-onset diabetes of parents, male gender, and an older parental age at delivery increased the risk of type 1 DM in siblings. Younger age at diagnosis in the index patient is the strongest predictor of the risk of type 1 diabetes in siblings (Gillespie, 2002). Information on autoantibody status and levels, HLA-conferred disease susceptibility, and insulin secretion and sensitivity are also useful in predicting the occurrence of disease in siblings. The cumulative risk of type 1 diabetes up to ages 10, 20, 30, 40 and 50 years in brothers and sisters of patients with childhood-onset diabetes is 1.5 per cent, 4.1 per cent, 5.5 per cent, 6.4 per cent, and 6.9 per cent, respectively (Harjutsalo et al., 2005).
Type 2 DM: Study based on disease-gene frequency model and the community-based prevalence data suggested a sibling recurrence ratio of 1.8–2.5 (Busfield, 2002). The life-time risk of developing the disease in offspring of one parent with type 2 DM is around 40%, greater if the mother is affected, and the risk rises to 70% if both the parents are affected (Ridderstrale & Groop, 2009). Thus, the empirical recurrence risks for first-degree relatives of type 2 DM are higher than those for type 1 DM. The increased risk of recurrence highlights the need for change in lifestyle and surveillance for early diagnosis. In addition to genetic contribution to DM, it has become obvious that the renal and retinal complications of DM also have genetic susceptibility and are currently an important research subject (Mishra et al., 2016). Though genetic variations are known for susceptibility to type 1 and 2 DM and are being explored in ongoing research works, genetic testing including HLA studies are currently not indicated in clinical settings.
To conclude, DM is a chronic debilitating illness with diverse etiologies. While type 1 and type 2 DM are well known and have a multifactorial inheritance, other monogenic forms of diabetes are often misdiagnosed as type 1 or 2 DM or remain underdiagnosed. Correct diagnosis with the help of molecular testing will aid in proper management and appropriate genetic counseling.
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2. Busfield F, et al. A genome wide search for type 2 diabetes-susceptibility genes in indigenous Australians. Am J Hum Genet 2002; 70: 349–357.
3. Erlich H, et al. HLA DR-DQ Haplotypes and Genotypes and Type 1 Diabetes Risk: Analysis of the Type 1 Diabetes Genetics Consortium Families. Diabetes 2008; 57: 1084–1092.
4. Gillespie KM. High familial risk and genetic susceptibility in early onset childhood diabetes. Diabetes 2002; 51: 210–214.
5. Harjutsalo V, et al. Cumulative incidence of type 1 diabetes in 10,168 siblings of Finnish young-onset type 1 diabetic patients. Diabetes 2005; 54: 563–569.
6. Mackay DJ, Temple IK. Transient neonatal diabetes mellitus type 1. Am J Med Genet C Semin Med Genet 2010; 154C: 335–342.
7. Mishra B, et al. Genetic components in diabetic retinopathy. Indian J Ophthalmol 2016; 64: 55–61.
8. Misra S, Owen KR. Genetics of Monogenic Diabetes: Present Clinical Challenges. Curr Diab Rep 2018; 18: 141.
9. Morris AP, et al. Large-scale association analysis provides insights into the genetic architecture and pathophysiology of type 2 diabetes. Nat Genet 2012; 44: 981–990.
10. Pihoker C, et al. Prevalence, characteristics and clinical diagnosis of maturity onset diabetes of the young due to mutations in HNF1A, HNF4A, and glucokinase: results from the SEARCH for Diabetes in Youth. J Clin Endocrinol Metab 2013; 98: 4055–4062.
11. Qi Q, et al. Genetic Determinants of Type 2 Diabetes in Asians. Int J Diabetol Vasc Dis Res 2015; Suppl 1:10.
12. Ridderstrale M, Groop L. Genetic dissection of type 2 diabetes. Mol Cell Endocrinol 2009; 297:10–17.
13. Rubio-Cabezas O, Ellard S. Diabetes mellitus in neonates and infants: genetic heterogeneity, clinical approach to diagnosis, and therapeutic options. Horm Res Paediatr 2013; 80:137–146.
14. Rudland VL. Diagnosis and management of glucokinase monogenic diabetes in pregnancy: current perspectives. Diabetes Metab Syndr Obes 2019; 12: 1081–1089.
15. Sarwar N, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Emerging Risk Factors Collaboration. Lancet 2010; 375: 2215–2222.
16. Varney M, et al. HLA DPA1, DPB1 Alleles and Haplotypes Contribute to the Risk Associated with Type 1 Diabetes. Diabetes 2010; 59: 2055–2062.
17. Vasileiou G, et al. Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome? Prenat Diagn 2019; 39:1136–1147.
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