Clinical AreaInternal medicine

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

If you cannot find the disease you are looking for, please use a known synonym in the search (also in English).

Molecular genetic diagnostics are also used to clarify the hereditary causes of numerous diseases in internal medicine. The aim here is to detect deviations from the reference genome (wild type) and then, if necessary, to differentiate between neutral variants and pathogenic mutations that are important for the physiological development and undisturbed function of all normal cells. The inheritance patterns of internal diseases are the basis of genetic counselling for patients, persons at risk and affected families. In the last 30 years thousands of genes have been characterized which cause internal diseases or contribute to their development. Current results of medical research have a direct impact on the diagnostic procedure in the laboratory and for genetic counselling. For example, mutations in independent genes on different chromosomes can cause clinically indistinguishable symptom patterns (locus heterogeneity). On the other hand, different mutations in one and the same gene lead to clinically apparently separate disease entities (allelic heterogeneity).

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

• monogenic diseases (autosomal or X-chromosomal inheritance)
• digenic diseases, which are only manifested when mutations are simultaneously present in heterozygous state in two different genes. Physiologically the two normal gene products together form functional heterodimers. Digenic inheritance affects ~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)

The multitude and complexity of internal diseases cannot be presented here in the necessary breadth. A whole series of disease groups that are to be included in internal medicine are dealt with under the disciplines of general medicine, angiology, diabetology, endocrinology, gastroenterology, haematology, cardiology, nephrology, oncology, pneumology and rheumatology etc. Therefore, the molecular genetics of diseases of the liver, coagulation and hypercholesterolemia are preferentially touched upon here. These diseases often occur sporadically - is there nevertheless a genetic (co-)cause? Hereditary internal diseases are demonstrably based on genetic changes and lead to various disturbances of proteins causing altered metabolic states. DNA diagnostics therefore often involves a step-by-step procedure in which the most frequently occurring mutations are initially tested before the very rare genetic causes are also identified in parallel approaches using expanded and cost-intensive panel procedures. Mutations found and all variants with unclear significance (VUS) are verified by DNA sequence analysis using the Sanger technique. Only three of the more common disease groups are listed subsequently.

Hereditary hemochromatosis is characterized by the excessive accumulation of iron in the tissue with respective damage. Besides systemic symptoms, liver symptoms, cardiomyopathy, diabetes and joint diseases occur. The diagnosis is based on increased serum ferritin, iron and transferrin saturation and it is usually confirmed by graded DNA tests or directly in the eight genes comprising panel. Depending on the mutated gene, hereditary hemochromatoses type 1-5 are distinguished: type 1, mutations in the HFE gene; type 2 (juvenile form), mutations in the HJV (type 2A) and HAMP genes (type 2B); type 3, mutations in the TFR2 gene; type 4 (ferroportin disease), mutations in the SLC40A1 gene; type 5, FTH1 gene. Very rare genetic disorders can cause iron overload in the liver, with the clinical picture dominated by symptoms of failure of other organs (e.g. anaemia in atransferrinaemia [TF gene defect] or neurological defects in systemic hemosiderosis in aceruloplasminaemia [CP gene mutations]). In Wilson's disease, copper accumulation occurs, because copper is insufficiently excreted. In addition to laboratory chemical tests, liver biopsy and ophthalmological examination, the genetic cause of this autosomal recessive hepatolenticular degeneration can be defined by detecting mutations in the ATP7B gene.

Primary hemostasis is already provided by the blood vessels, which contract under pressure/injury. Platelets attach to the inner wall of the vessel and stick together. For the analysis of genetic defects in primary hemostasis, DNA panels are available for macrothrombocytopenia, platelet dysfunction/thrombocytopathies and thrombocytopenia. In the actual blood clotting process >30 different factors are involved. Ultimately, insoluble fibrin is formed from the precursor fibrinogen. In connection with coagulation disorders that are only initially or insufficiently diagnosed, sometimes exclusively the hereditary von Willebrand-Jürgens syndrome is analyzed molecularly on the basis of the comparatively large VWF gene. Nevertheless very extensive panels are available for differential diagnostic clarification, including the individual genes for the factors F2, F5, F7, F8, F9, F10, F11, F12, F13A1, the fibrinogen polypeptides and many more, thus a total of at least two dozen different proteins.

Familial hypercholesterolemia (FH) is an autosomal-dominantly inherited disorder of the lipid metabolism mainly caused by increased low density lipoprotein (LDL). The fundamental defect is overproduction of hepatic VLDL particles, which initiates lipoprotein changes with the end result of higher LDL levels. FH is a major risk factor especially for arteriosclerotic and coronary heart disease as well as cerebral circulatory disorders and thromboses. On the one hand, this metabolic disorder is based on >1000 mutations in the LDL receptor gene. Mutations in the apolipoprotein B 100 and LDL receptor adaptor protein genes lead to a disturbed clearance of LDL cholesterol. Heterozygous forms of FH occur with ~2‰ prevalence, in homozygosity very rarely but with pronounced clinical symptoms in early childhood comprising xanthomas, xanthelasmas, corneal "greisenbogen" and arteriosclerosis. Gene panel analysis heretofore is available.