This article examines the implications for parents and family members when a child is diagnosed with a genetic syndrome. In particular, it describes how practices of understanding are shaped when the syndrome occurs 'de novo', that is, when it has not been inherited from either parent and where there is no family history. Despite a significant body of research exploring the social implications of genetic disease and diagnostic technologies, sociological understandings of the implications of a de novo mutation are considerably limited. This article draws on semi-structured interviews conducted with twenty three parents of children diagnosed with 22q11 deletion syndrome, a syndrome associated with high rates of de novo cases. Three themes were identified: 'lay' understandings of genetics; making genetic connections and genetic gatekeeping. Overall, this article articulates and confirms the enduring significance of family for contextualising health and illness.