Beyond the Index Case: A Practical Framework for Cascade Family Screening in Hereditary Angioedema

Abstract Hereditary angioedema (HAE) is a genetic disorder characterised by recurrent cutaneous or submucosal oedema. Most cases are caused by pathogenic SERPING1 variants (types I and II), while a smaller subset presents with normal C1-inhibitor (C1-INH) levels and function (HAE-nC1INH). Despite its potentially life-threatening attacks, HAE remains under-diagnosed owing to inconsistent screening practices, low clinical awareness, poor patient acceptance, and resource limitations, resulting in diagnostic delays and preventable morbidity. Although international guidelines recommend family screening to identify at-risk relatives, no standardised protocol exists for its systematic implementation. Cascade family screening offers a structured approach to trace and test all known at-risk relatives across generations. Complementing this strategy, dried blood spot (DBS) assays provide a less invasive, cost-effective alternative to conventional serological testing, with particular utility in resource-limited settings. In this review, we critically appraise current screening methodologies, synthesise emerging evidence on cascade family screening and DBS-based diagnostics, and propose an actionable clinical flowchart to standardise identification, testing, and patient education from index case detection through multi-generational family screening.