Clinical AreaDiabetology

Here you will find the disease-related gene panels available for the clinical area specified above.

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Genetic diagnostics are used to clarify the hereditary causes of diabetic diseases. The aim here is to identify deviations from the reference genome ("wild type") and then, if necessary, to distinguish between neutral variants and pathogenic mutations that are important for the physiological development and undisturbed function of all normal cells and their possible degeneration. The inheritance patterns of diabetic diseases are the basis of genetic counselling for patients, persons at risk and affected families. Over the last 30 years dozens of genes that cause or contribute to the development of diabetic diseases have been characterized. Current results of diabetological research have a direct impact on the diagnostic procedure in the laboratory and in genetic counselling. For example, mutations in independent genes on different chromosomes can cause clinically indistinguishable forms of diabetes such as MODY (Maturity-Onset Diabetes of the Young [“locus heterogeneity”]). On the other hand, different mutations in one and the same gene lead to clinically apparently separate disease entities (PDX1 gene mutations cause MODY type IV and pancreatic agenesia [“allelic heterogeny”]).

Formal genetically and etiologically the following groups of genetic diseases can be distinguished:

• monogenic diseases (autosomal or X-chromosomal inheritance)
• digenic diseases, which only manifest when mutations are simultaneously present in heterozygous state in two different genes. The two normal gene products together form functional heterodimers. Digenic inheritance concerns 3% of hereditary diseases in addition to the classic autosomal and X-linked diseases.
• mitochondrial diseases (maternal or autosomal inheritance)
• multifactorial diseases (interaction of several to many genes plus environmental factors)

Diabetic signs often develop sporadically - is there a genetic (co-)cause? Hereditary diabetic diseases are demonstrably based on genetic changes and lead to various changes in the proteins that are linked to diabetic metabolic states. DNA diagnostics therefore often involves a step-by-step procedure in which the most frequent mutations are first tested, before the very rare genetic causes are identified in parallel approaches using more extensive and cost-intensive panel procedures. Mutations found or all variants with unclear significance (VUS) are verified by DNA sequence analysis using the Sanger technique. Special forms of diabetic disease are treated within other specific medical disciplines, e.g. endocrinological diagnostics. The following are therefore only a few of the other more common disease groups.

Type 1 diabetes is usually immunologically mediated or idiopathic, i.e. mostly without scientifically objectifiable causes. Genetically, the HLA association with the alleles DQB103:02 and DQB102:01 as predisposing factors in large cohorts has been statistically proven for decades. The allele DQB106:02 has a protective effect, whereas the predisposing alleles in single doses increase the relative risk 5-fold, the combination of DQB102:01/ DQB1*03:02, however, >25-fold. Similarly frequent as type 2 diabetes, adolescents may suffer from the non-immunologically caused but genetically determined MODY (see below). Other forms of diabetes mellitus in childhood include the also genetically fixed neonatal diabetes and diabetes in cystic fibrosis as well as other rare syndromes (see below). Pregnant women with diabetes may have pathophysiological conditions as complex as other forms of diabetes, a combination of genetic, epigenetic and environmental influences.

While for transient neonatal diabetes only four genes with their mutations are currently proven to be really relevant, for veritable neonatal diabetes more than two dozen of genes are pending for comprehensive investigation in the panel. A good dozen of these genes stands the focus of molecular genetic diagnostics. Complex syndromes such as Alström, Prader-Willi syndrome, Wolfram syndrome type 1 + 2, but also chromosomal defects (trisomy 21, Klinefelter and Turner syndrome) as well as Friedreich's ataxia and myotonic dystrophy can often be associated with diabetic signs. Neonatal hyperglycaemia may also be associated with congenital hypothyroidism. For further differential diagnostic questions, e.g. MODY (see below), gene panels could also be used in combination.

Up to 14 genetically differentiable forms of diabetes are currently grouped under MODY, sharing autosomal dominant inheritance and pathophysiologically primary insulin secretion defects of the pancreatic B cells. Not all genes of these subforms have been shown to be useful components of panels for several reasons. If the clinical diagnosis remains less specific, several gene panels are also available for differential diagnosis depending on the disease group