Article: 1 of 2
Update: Apr 06, 2021
Author(s): Tinschert, Sigrid
In vascular malformations, both heritable mutations (germline mutations, constitutional mutations) and non-heritable mosaic mutations (postzygotic mutations, somatic mutations) play a role. The genetic principles are summarized in this chapter, and reference is only made to specific diseases in exceptional cases (in the case of genetic mosaics).
Diseases caused by mutations of a single gene are called monogenic diseases. Inheritance occurs according to Mendelian laws (Mendelian inheritance).
The human genome is organized into 46 chromosomes. With the exception of the sex chromosomes in males, the chromosomes exist as 23 pairs of identical (homologous) chromosomes. One chromosome in a pair comes from the mother, the other from the father. The pairs of genes corresponding to each other are called alleles; they are located in the same place on the homologous chromosomes (= gene locus). The two alleles can be identical (homozygous) or different (heterozygous). If both alleles carry different mutations, this is called compound heterozygosity. Since males, unlike females, have two non-homologous sex chromosomes X and Y, the X chromosomal genes have no homologous counterpart on the Y chromosome; they are “hemizygous” (exception: genes of the pseudo-autosomal region).
The distribution (segregation) of parental genotypes in their offspring is determined by the alleles of the parents and is subject to Mendelian laws.
In a genetic family tree, the most important genetic information of a family has to be clearly presented. Uniform and unambiguous symbols should be used. Female persons are represented as circles, males as squares. If the person is diseased, the symbol is marked (e.g., marked in black).
In contrast to females, males have only one allele each for all X-linked genes (exception: pseudo-autosomal region). If the mutated gene is localized on the X chromosome, this is referred to as a hemizygous mutation in males and a heterozygous mutation in females. In females only, a wild-type allele is to be found at the second locus in this case; this can more or less compensate for the effect of the mutated allele. Individuals who carry a mutation without having a recognizable disease are “conductors”.
A characteristic feature of X-linked inheritance is a sex-dependent expression. The male sex is more severely affected. In typical X-linked inheritance, several affected males occur in successive generations, each linked via the female line.
Genetic mosaics are causative in many vascular anomalies, whether occurring in isolation or as part of complex syndromes.
A mosaic in the biological sense is an organism consisting of two or more genetically different cell populations originating from one zygote. The cause of the genetic differences between the cell populations may be early postzygotic or late (somatic) mutations. The timing of the mutation(s) determines the extent (severity) and pattern of changes. Mosaics are particularly conspicuous on the skin. A typical example of a cutaneous vascular mosaic, early postzygotic in origin, is nevus flammeus. Late somatic mutations, which in addition to a germline mutation lead to complete loss of the corresponding gene product, play a major role not only in tumorigenesis (second-hit hypothesis = Knudson hypothesis) but also in vascular malformations. For example, somatic mutations have a role in the development of teleangiectasias in Osler syndrome or RASA1-associated CM-AVM.
Furthermore, the appearance (phenotype) is determined by (a) the expression pattern of the gene (in which tissues it is expressed), (b) the cell type (its tissue affiliation) in which the mutation event occurred, (c) the degree of differentiation of the cell at the time of mutation, (d) the localization of the mutant cell in the body.
In the context of isolated vascular malformations and vascular malformation syndromes, the early postzygotic mosaics that lead to segmental patterns play a particularly important role. Two types are distinguished, the common type 1 and the rare type 2 mosaic.
Type 1 mosaic is based on an early embryonic activating mutation of an agonist of a signaling cascade (e.g., PIK3CA or AKT1 in the phosphatidylinositol (PI)3-kinase (PIK3)/AKT/mTOR pathway). Such early heterozygous mutations lead to regional and extensive lesions. They are severe mutations that are compatible with life only in a mosaic fashion. Therefore, these diseases are not hereditary. Type 1 mosaicism is the genetic basis of most vascular malformation syndromes involving overgrowth.
Type 2 mosaic is based on a pre-existing constitutional (inherited) loss-of-function mutation of an antagonist of the corresponding signaling cascade (e.g., PTEN in the phosphatidylinositol (PI)3-kinase (PIK3)/AKT/mTOR pathway or RASA1 in the RAS-MAPK pathway), to which an additional early embryonic second-hit mutation is added. Complete loss of function of the gene due to mutation of both alleles results in a large-scale regional phenotype. The constitutional mutation is hereditary − therefore type 2 mosaic disease can (rarely) occur in families; the concept of this so-called paradominant inheritance was developed by Rudolf Happle in 1992.
Significance for mutation detection: The mutation of type 1 mosaic is only detectable in the affected tissue and usually not in the blood. In type 2 mosaic, only the constitutional mutation is present in the blood. However, its identification is sufficient for diagnosis. The second hit of the type 2 mosaic is also only detectable in the affected tissue.
The task of genetic counseling is to inform patients and their families about existing genetic diseases. Genetic counseling is performed by a specially qualified physician; in Germany this is usually a specialist in human genetics or a physician who has acquired the additional qualification in medical genetics. This must be distinguished from specialist genetic counseling which, according to the German Genetic Diagnostics Act (GenDG), can be performed by specialists in other fields within the scope of their respective field, except in the context of predictive examinations.
The specific content of the human genetic consultation depends on the individual issues of the person seeking advice. In essence, it is about the cause, prognosis and probability of recurrence of a disease. These questions can only be answered on the basis of a confirmed and etiologically oriented diagnosis. Diagnosis (confirmation) is therefore at the center of every genetic counseling session.
In order to establish the diagnosis, the patient's own medical history is first collected, findings are reviewed and a family history (genetic family tree) covering at least three generations is compiled.
Depending on the problem, physical examinations from a clinical and genetic point of view (“phenotype analysis”) are performed, if necessary. Further examinations are coordinated with other specialist departments (e.g., radiological imaging, biochemical diagnostics) and special genetic laboratory tests (karyotyping, molecular genetic tests) are arranged. If rare malformation complexes are involved, an attempt is made to classify the symptoms by comparing them with databases and the specialist literature.
If the diagnosis is known, the current state of knowledge about the respective clinical picture is communicated to those seeking advice. This also includes recommendations for the avoidance or treatment of disease-specific complications; a cure is usually not possible. Probabilities of disease for the person seeking advice and family members are discussed. If there is an explicit wish to have a child, possibilities of prenatal diagnostics are discussed.