Somatic mosaicism in hypothalamic hamartoma

Somatic mosaicism is the usual genetic mechanism in cancers but was generally regarded as a rarity in non-malignant neurological disorders. Over the last decade, it has been shown to be the major cause of a variety of brain malformation syndromes and developmental tumors. It is studied by analyzing DNA samples from brain tissue removed for the surgical treatment of epilepsy, compared to samples from peripheral tissues. It has been shown to be relevant for unilateral malformations and developmental tumors associated with epilepsy. This has been extended to epilepsy with hypothalamic hamartoma in sporadic cases, including single somatic variants in sonic hedgehog pathway genes and two-hit germline and somatic variants in primary cilia genes. As some of the genes are known to cause hypothalamic hamartoma in rare germline disorders, these findings establish a somatic to germline continuum.