KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation. This study identified de novo missense variants in KCTD15 in two families presenting with a clinically similar, rare phenotype involving frontonasal mass and cutis aplasia or sparse hair. Structural and biophysical analyses demonstrated that these substitutions act through a dominant negative mechanism by disrupting the pentameric assembly of the BTB domain. The KCTD15 substitutions and phenotype clinically overlap with BTB domain substitutions in the paralogue KCTD1, which cause scalp-ear-nipple (SEN) syndrome, consistent with partially overlapping functions. KCTD15 is a new human disease gene that should be particularly scrutinised in patients presenting with frontonasal mass. (By Professor Alex N Bullock and Professor Andrew O M Wilkie, https://jmg.bmj.com/content/early/2024/01/30/jmg-2023-109531 )