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Study identifies de novo missense variants in KCTD15 associated with frontonasal mass phenotype.



KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation. This collaborative study from the groups of Profs Alex Bullock and Andrew Wilkie 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.