Pathogenic mutations are involved in alterations of the genetic material that causes illnesses. Basically, "too much" or "to little" genetic information leads to disorders. In other words, if the genetic material is not balanced, disease ensues. Most mutations lead to altered gene products. As consequences these can be disturbances in individual metabolic tasks but also alterations of the entire phenotype.
One distinguishes between two kinds of mutations:
In gene mutations disruptions occur within a single gene. If whole portions of chromosomes are disrupted, one speaks of structural anomalies within a chromosome or, if the number of chromosomes has changed, of trisomies, monosomies, or, more generally of aneuploidies or numerical chromosomal aberrations.
It is important to state that most chromosome deviations arise randomly during gamete formation through non-disjunctions or chromosome breaks. Either such disorders (deletions, duplications, isochromies of individual chromosomes = disorders of the chromosome structure; trisomies, monosomies = disorders of the number of chromosomes) have immediate clinical consequences or they remain undiscovered in this generation because the genetic material, despite rearrangements, is still present in its entirety, i.e., is balanced. Nevertheless, balanced chromosomal aberrations lead to defective gamete formations. Through this, the disorder may appear phenotypically only in the next generation or the one after that. For example, fusions of acrocentric chromosomes 14/21 (= robertsonian translocations) can lead to a hereditary trisomy 21 or Down syndrome.
A smaller part of chromosomal deviations takes place after the fertilization in a cell line. This leads to mosaic forms.
With abnormalities and diseases one has again and again seen that a genetic disposition is indeed present (accumulation of diseases in families). Either several genes must be present, however, for the expression of the symptom (disease or abnormality) (=> polygeny) or still other influences must play a role that a disease breaks out or an abnormality appears (=> multifactorial inheritance). In addition, in certain mutations, genetic imprinting has a large influence on the phenotypes.
In the clinic, children with a deviating number or structure of their chromosomes have mostly multiple abnormalities, often combined with mental retardation. If smaller gene regions are affected, the disorders, depending on their severity, can appear only later. The following clinical criteria indicate possible chromosomal aberrations:
- Pre- and postnatal growth disorders
- Mental retardation
- Dysmorphic signs.
If there are indications in the anamnesis for an increased appearance of congenital abnormalities, monogenetic hereditary diseases or habitual miscarriages, genetic counseling should definitively be made available.