In den letzten Jahren haben „De-novo“-Mutationen – also solche, die von keinem der beiden Elternteile vererbt wurden – in der pädiatrischen Neurologie aus verschiedenen Gründen besondere Bedeutung erlangt:
Sie sind für die Mehrzahl der Fälle genetisch identifizierbarer neurologischer Entwicklungsstörungen verantwortlich.
Sie sind für die schwersten Fälle zuständig.
Dies lässt sich durch eine Verzerrung aufgrund der natürlichen Selektion erklären. Vererbte Erkrankungen sind in der Regel weniger schwerwiegend als „de novo“-Erkrankungen, da sie bedeuten, dass der Betroffene in der Lage war, das Erwachsenenalter zu erreichen, einen Partner zu finden und sich fortzupflanzen. Daher haben Varianten, die in der Allgemeinbevölkerung bestehen bleiben und häufig bei gesunden Trägern vorkommen, geringere phänotypische Auswirkungen, obwohl die Tatsache, dass eine Variante „de novo“ ist, keine Pathogenität garantiert.
Sie stellen das klassische Paradigma der genetischen Krankheit als Erbkrankheit in Frage.
Dies stellt die relative Bedeutung der Familienanamnese beim Verdacht auf eine genetische Erkrankung in Frage, da deren Fehlen kein Ausschlusskriterium darstellt.
Das Risiko einer De-novo-Mutation hängt davon ab Alter der Eltern.
Durch Genomstudien wissen wir derzeit, dass gesunde Menschen etwa 50–100 De-novo-Mutationen tragen.
Daher ist es nicht ungewöhnlich, dass es Fälle komplexer Phänotypen gibt, bei denen mehrere Mutationen zu überlappenden Phänotypen mit größerem Schweregrad führen (doppelter Ärger), woraus sich der Begriff „Mutationslast“ ableitet.
Dies stellt das klassische Paradigma der monogenetischen Erkrankung in Frage.
Auf diese Weise kann die Rolle der genetischen Varianten, die jedes Individuum aufweist, eine polygene Vererbung (quantitativ, Risikofaktor) darstellen, wenn die Varianten nur geringe phänotypische Auswirkungen haben, oder eine monogenetische Krankheit, wenn der Ort und die Folgen der Variante schwerwiegende klinische Auswirkungen haben.
Sie können jenseits der Vorstellung auftreten und sind daher die Ursache dafür Verfassungsmosaiken.
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