Clinical AreaPaediatrics

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 used to clarify the hereditary causes of childhood and adolescent 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 functioning of the child's organism. The inheritance patterns of such diseases are the basis of genetic counselling for parents, persons at risk and affected families. In the last 30 years, several thousand genes have been characterised which cause rare diseases or contribute to the development of these diseases. Current research results have a direct impact on the diagnostic procedure in the laboratory and in genetic counselling. For example, mutations in independent mitochondrial and nuclear genes on different chromosomes can cause clinically indistinguishable forms of mitochondriopathies ("locus heterogeneity"). On the one hand, different mutations in one and the same gene MPZ (myelin protein zero) lead to 3-4 clinically severable forms of hereditary motor and sensory neuropathies (axonal, demyelinating, intermediate HMSN) and, on the other hand, to the severe Déjérine-Sottas syndrome ("allelic heterogeneity").

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

• monogenic diseases (autosomal or X-chromosomal inheritance)
• digenic hereditary diseases, which only manifest themselves when mutations are simultaneously in heterozygous state in two different genes. 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)

Congenital malformations often appear sporadically - is there a genetic (co-)cause? Several thousand inherited disorders are demonstrably based on genetic changes and lead to disorders in the proteins that build up the child's organism and are essential for its further development. 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 also identified in parallel approaches using 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.

Child and adolescent medicine comprises at least two thirds of all monogenic diseases. Therefore, only a few of the more frequent disease groups are listed below as examples. Relevant additional information can therefore be found in other medical disciplines such as internal medicine/cardiology, ophthalmology, dermatology, ENT, orthopaedics, urology etc.

A conspicuous newborn screening can usually be classified diagnostically by means of single gene analysis according to the metabolite profile or the endocrinological findings. In neuropaediatrics, in the majority of diseases, one or more genetic factors are involved in the causal pathogenesis of the developmental disorder. Often numerical and structural chromosomal defects are detectable as well as genetic mutations that cause monogenic syndromes (e.g. the relatively common Fragile X syndrome). Submicroscopic DNA duplications (e.g. PMP22 gene duplication leads to HMSN1A) or deletions as in velocardiofacial or Williams-Beuren syndrome are clarified with array or MLPA diagnostics. Diagnostic gene panels for more complex developmental disorders such as congenital malformations of the skeleton, organs or dysmorphia comprise up to several hundred genes, which are sequenced in parallel. Initially, only those genes that appear usually related with the clinical picture are analysed. The individual gene panels can be used separately or in combination for diagnostic purposes.

Neuromuscular diseases affect the muscles, the anterior horn cells of the spinal cord or the motor end plates and lead to the primary symptom of muscle weakness. The differential diagnosis of neuromuscular diseases requires not only a thorough clinical examination in the muscle centre but also a detailed family tree, electrophysiology and muscle biopsy with specialised (immune) histology. In many cases, however, only molecular genetic analysis allows the exact diagnosis to be determined. Examples of neuromuscular diseases are dystrophinopathies (Duchenne / Becker disease), numerous forms of limb girdle muscular dystrophies, myotonic dystrophies, muscle atrophies (spinal muscular atrophy, SMA) and spinobulbar muscular atrophy (Kennedy type; SBMA). For the abovementioned and many other diseases of this type, the heredity patterns are precisely known, and the genetic defects are directly detectable. If the clinical diagnosis remains less specific, several gene panels are available depending on the disease group.

Mutations in the mitochondrial DNA (mtDNA) are special - they are only inherited maternally. And in a given cell, different mtDNA copies can be present with and without mutations (heteroplasmia). Only when a certain threshold value of these functional cell organelles is reached and a high proportion of mutated mtDNA is present, does the loss of mitochondrial function and the disease symptoms manifest. Mitochondrial clinical pictures are often particularly demanding in terms of differential diagnosis and will therefore often have to be classified with more expanded gene panels.

Primary immunodeficiency diseases (PIDD) are not so rare (1/1 200 to 1/2 000; however, they are caused by mutations in more than 300 genes. PIDD can occur syndromally, be characterised by antibody deficiency, autoimmunity or autoinflammation, be generally variable ("common variable ID"), combined (SCID) or lymphoproliferative, or can also affect innate immunity or certain cell types (neutrophil granulocytes, "natural killer" cells). Many of the monogenic primary immunodeficiencies defined so far show variable expressivity (severity of symptoms) and penetrance (penetrating power of the mutation). Patients with one and the same mutation can exhibit very different symptoms; similar clinical symptoms may be due to mutations in different genes. Meaningful interpretation of genetic data can usually only be achieved by considering the clinical picture in the context of the immunological findings and the relevant literature. Advantages of genetic diagnostics include the unambiguous identification of patients, better prognostic assessment and special therapy planning (pharmacotherapy, stem cell transplantation, gene therapy).

• Intelligence impairment
• Mental disability These four terms are used almost synonymously here, although one or other term has sometimes been attributed a lack of political correctness. Mental retardation (MR) is usually defined as a substantial reduction in cognitive and adaptive abilities, starting in early childhood and having an IQ below 70, with a prevalence of up to 2% for milder forms and up to 0.5% for IQs below 50. In addition to chromosomal disorders such as Down syndrome, especially submicroscopic deletions and duplications have been known for a long time as causes for intellectual deficits. It is estimated that mutations in 1000-2000 different genes can lead to autosomal dominant inherited mental retardation (ADMR), more than 400 genes have been identified so far, possibly most of the ADMR genes already. For X-linked MR >150 genes are defined. Autosomal recessive MR (ARMR) could be caused by mutations in >3000 genes. A recent study concluded that the MR risk for offspring of cousin-cousin pairs is up to 4.25 times higher. As a result, the corresponding gene panels are very large and can be subdivided according to numerous accompanying symptoms.