В последние годы мутации «de novo», не унаследованные ни от одного из родителей, приобрели особую актуальность в детской неврологии по нескольким причинам:
Они ответственны за большинство случаев генетически идентифицируемых нарушений нервного развития.
Они несут ответственность за самые серьезные случаи.
Это объясняется тем, что существует предвзятость, обусловленная естественным отбором. Наследственные заболевания обычно менее серьезны, чем болезни «de novo», поскольку они подразумевают, что человек смог дожить до взрослого возраста, спариваться и размножаться. Таким образом, варианты, которые остаются в общей популяции и часто обнаруживаются у здоровых носителей, оказывают меньшее фенотипическое воздействие, хотя тот факт, что вариант является «de novo», не гарантирует патогенность.
Они ставят под сомнение классическую парадигму генетических заболеваний как наследственной болезни.
Это ставит под сомнение относительную важность семейного анамнеза при подозрении на генетическое заболевание, поскольку его отсутствие не является критерием исключения.
Риск мутации de novo зависит от возраст родителей.
Благодаря геномным исследованиям мы в настоящее время знаем, что здоровые люди являются носителями около 50-100 мутаций de novo.
Поэтому нередки случаи сложного фенотипа, при которых множественные мутации приводят к перекрывающимся фенотипам большей тяжести (двойная проблема), породив понятие «мутационная нагрузка».
Это ставит под сомнение классическую парадигму моногенетического заболевания.
Таким образом, роль генетических вариантов, представленных у каждого человека, может представлять собой полигенное наследование (количественное, фактор риска), когда варианты оказывают незначительное фенотипическое влияние, или моногенетическое заболевание, когда расположение и последствия варианта оказывают серьезное клиническое воздействие.
Они могут возникать сверх зачатия, поэтому являются причиной конституциональный мозаицизм.
19955111
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1
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50
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4863
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