Mutations in KCTD1 Cause Scalp-Ear-Nipple Syndrome

Scalp-ear-nipple (SEN) syndrome is a rare, autosomal-dominant disorder characterized by cutis aplasia of the scalp; minor anomalies of the external ears, digits, and nails; and malformations of the breast. We used linkage analysis and exome sequencing of a multiplex family affected by SEN syndrome to identify potassium-channel tetramerization-domain-containing 1 (KCTD1) mutations that cause SEN syndrome. Evaluation of a total of ten families affected by SEN syndrome revealed KCTD1 missense mutations in each family tested. All of the mutations occurred in a KCTD1 region encoding a highly conserved bric-a-brac, tram track, and broad complex (BTB) domain that is required for transcriptional repressor activity. KCTD1 inhibits the transactivation of the transcription factor AP-2 alpha (TFAP2A) via its BTB domain, and mutations in TFAP2A cause cutis aplasia in individuals with branchiooculofacial syndrome (BOFS), suggesting a potential overlap in the pathogenesis of SEN syndrome and BOFS. the identification of KCTD1 mutations in SEN syndrome reveals a role for this BTB-domain-containing transcriptional repressor during ectodermal development.National Institutes of Health National Human Genome Research InstituteLife Sciences Discovery FundWashington Research FoundationMassachusetts Gen Hosp, Cutaneous Biol Res Ctr, Charlestown, MA 02129 USAUniv Washington, Dept Pediat, Seattle, WA 98195 USAUniv Washington, Dept Genome Sci, Seattle, WA 98195 USAUniv Western Sydney Macarthur, Sch Med, Campbelltown, NSW 2560, AustraliaGenet Learning Disabil Serv, Newcastle, NSW 2298, AustraliaJohns Hopkins Univ, Sch Med, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Clin Genet Ctr, BR-04021001 São Paulo, BrazilPontificia Univ Catolica Parana, Dept Internal Med, BR-1155 Curitiba, Parana, BrazilWestern Gen Hosp, South East Scotland Clin Genet Serv, Edinburgh EH4 2XU, Midlothian, ScotlandUniv Florence, Dept Genet & Mol Med, I-50132 Florence, ItalyHop Necker Enfants Malad, Dept Genet, INSERM, U781, F-75015 Paris, FranceUniv Paris Descartes Sorbonne Paris Cite, Inst Imagine, F-75015 Paris, FranceHop Cote Nacre, CHU Caen, Serv Genet, F-14033 Caen 9, FranceUniv Connecticut, Ctr Hlth, Dept Reconstruct Sci, Farmington, CT 06030 USABoston Childrens Hosp, Dept Plast & Oral Surg, Boston, MA 02115 USATreuman Katz Ctr Pediat Bioeth, Seattle Childrens Res Inst, Seattle, WA 98101 USAUniversidade Federal de São Paulo, Dept Morphol & Genet, Clin Genet Ctr, BR-04021001 São Paulo, BrazilNational Institutes of Health National Human Genome Research Institute: 1U54HG006493National Institutes of Health National Human Genome Research Institute: 1RC2HG005608National Institutes of Health National Human Genome Research Institute: 5RO1HG004316Life Sciences Discovery Fund: 2065508Life Sciences Discovery Fund: 0905001Web of Scienc