BTB domain mutations perturbing KCTD15 oligomerisation cause a distinctive frontonasal dysplasia syndrome

J Med Genet. 2024 Apr 19;61(5):490-501. doi: 10.1136/jmg-2023-109531.


Introduction: KCTD15 encodes an oligomeric BTB domain protein reported to inhibit neural crest formation through repression of Wnt/beta-catenin signalling, as well as transactivation by TFAP2. Heterozygous missense variants in the closely related paralogue KCTD1 cause scalp-ear-nipple syndrome.

Methods: Exome sequencing was performed on a two-generation family affected by a distinctive phenotype comprising a lipomatous frontonasal malformation, anosmia, cutis aplasia of the scalp and/or sparse hair, and congenital heart disease. Identification of a de novo missense substitution within KCTD15 led to targeted sequencing of DNA from a similarly affected sporadic patient, revealing a different missense mutation. Structural and biophysical analyses were performed to assess the effects of both amino acid substitutions on the KCTD15 protein.

Results: A heterozygous c.310G>C variant encoding p.(Asp104His) within the BTB domain of KCTD15 was identified in an affected father and daughter and segregated with the phenotype. In the sporadically affected patient, a de novo heterozygous c.263G>A variant encoding p.(Gly88Asp) was present in KCTD15. Both substitutions were found to perturb the pentameric assembly of the BTB domain. A crystal structure of the BTB domain variant p.(Gly88Asp) revealed a closed hexameric assembly, whereas biophysical analyses showed that the p.(Asp104His) substitution resulted in a monomeric BTB domain likely to be partially unfolded at physiological temperatures.

Conclusion: BTB domain substitutions in KCTD1 and KCTD15 cause clinically overlapping phenotypes involving craniofacial abnormalities and cutis aplasia. The structural analyses demonstrate that missense substitutions act through a dominant negative mechanism by disrupting the higher order structure of the KCTD15 protein complex.

Keywords: Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Exome Sequencing; Mutation, Missense; Structural Homology, Protein.

MeSH terms

  • Abnormalities, Multiple
  • BTB-POZ Domain*
  • Co-Repressor Proteins / genetics
  • Craniofacial Abnormalities* / genetics
  • Ectodermal Dysplasia
  • Face* / abnormalities
  • Humans
  • Mutation, Missense / genetics
  • Syndrome


  • Co-Repressor Proteins
  • KCTD1 protein, human

Supplementary concepts

  • Frontonasal dysplasia