LAUSR

While representing a significant improvement, the introduction of next‐generation sequencing in genetic diagnosis also prompted new challenges. Despite widely recognized consensus guidelines for the interpretation of sequence variants, many variants remain unclassified or are discordantly interpreted. In heritable thoracic aortic aneurysms with dissection (HTAAD), most cases are caused by a heterozygous, private missense mutation, possibly contributing to the relatively common reports of variants with uncertain significance in this group. Segregation analysis necessitates advanced likelihood‐based methods typically inaccessible to non‐experts and is hampered by reduced penetrance, possible phenocopies, and non‐availability of DNA from deceased relatives.