Ces dernières années, les mutations « de novo », celles qui ne sont héritées d’aucun des parents, ont acquis une importance particulière en neurologie pédiatrique, pour plusieurs raisons :
Ils sont responsables de la majorité des cas de troubles du développement cérébral identifiables génétiquement.
Ils sont responsables des cas les plus graves.
Cela s'explique par le fait qu'il existe un biais dû à la sélection naturelle. Les maladies héréditaires sont généralement moins graves que les maladies « de novo », car elles impliquent que l'individu a été capable de vivre jusqu'à l'âge adulte, de s'accoupler et de se reproduire. De cette manière, les variantes qui restent dans la population générale et que l'on retrouve fréquemment chez les porteurs sains, produisent moins d'impact phénotypique, même si le fait qu'une variante soit « de novo » ne garantit pas la pathogénicité.
I contestent le paradigme classique de la maladie génétique comme maladie héritée.
Cela remet à l'importance relative des antécédents familiaux dans le diagnostic d'une maladie génétique, car leur absence ne constitue pas un critère d'exclusion.
Le risque de mutation novatrice dépend de la âge parental.
À travers les études génomiques, nous savons actuellement que les personnes saines sont porteuses d'environ 50-100 mutations novatrices.
Par conséquent, il est courant d'avoir des cas de phénotype complexe dans lesquels plusieurs mutations entraînent des phénotypes superposés de gravité accrue (problème double), donnant naissance au concept de « charge mutationnelle ».
Cela remet à la théorie classique de l' maladie mono-génétique.
Voici comment les variantes génétiques que chaque individu présente peuvent représenter une héritage polygénique (quantitatif, facteur de risque) lorsque les variantes produisent peu d'effet phénoménal, ou une maladie monogène, lorsque la localisation et les conséquences de la variante provoquent une répercussion clinique grave.
Peuvent se produire à l'extérieur du conçu, ce qui les rend la cause des mosaïsmes constitutionnels.
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