Fig. 3

Schematic summary of the genetic etiology of the families, categorized into three groups. We classified the families into three distinct groups based on the clinical actionability of the genetic findings, as illustrated systematically in the upper panel and for the 36 families in the lower panel. The first group represents families with a pathogenic variant identified as the cause of disease, passing a clinically actionable threshold where results could be returned to the patients and relatives. The second category includes families with (possible) genetic risk factors (APOE, VUS, and PRS). These are not clinically actionable (i.e., these families are clearly burdened by genetic risk factors, but the complete cause is uncertain). Possibly, additional components of the genetic risk remain unidentified. The last group comprises families without any genetic risk factor currently identified, despite early onset and positive family history. The lower panel shows that we can genetically explain eight families, suspect a partially identified polygenic/multifactorial etiology in 19 families, whereas nine remain completely unresolved