Mutations in KCTD1 cause scalp-ear-nipple syndrome

Abstract

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-2α (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.

Figure 1

Characteristic Physical Findings in Individuals with SEN Syndrome Clinical characteristics of SEN syndrome include cutis aplasia of the vertex of the scalp (A, B, and D), minor external ear defects, such as overfolded helix and anteverted ears (C and F), and aplasia of the nipples and sparse or absent secondary sexual hair (G and H). Less common findings include syndactyly and nail dysplasia (E) and craniofacial malformations such as telecanthus, a broad, flat nasal bridge, and frontal bossing (F). Case identifiers E:III-1 (A–C), F:II-1 (F), J:I-1 (D and H), and J:II-1 (E and G) correspond to those in Table 1 and Table S1, where a detailed description of the phenotype of each affected individual is provided.

Figure 2

Pedigrees of Families A–J Pedigrees illustrating the relationships and affected status of ten families affected by SEN syndrome. Case identifiers correspond to those in Table 1 and Table S1. Grey dots indicate individuals who underwent exome sequencing. Plus signs (+) indicate individuals in whom mutations were identified, and minus signs (–) indicate individuals in whom no mutation was found. Family A individuals with a plus or minus sign (except individuals IV-14 and V-6) were also included in the linkage analysis.

Figure 3

Genomic Structure and Allelic Spectrum of KCTD1 Mutations that Cause SEN Syndrome KCTD1 is composed of five exons that encode UTRs (orange) and protein-coding-sequence domains (blue), including a BTB domain (red). Arrows indicate the locations of ten different mutations found in ten families affected by SEN syndrome. Carrots indicate mutations that were confirmed to be de novo. Deduced amino acid sequences of partial KCTD1 in multiple species are shown. Locations of amino acid residues affected by KCTD1 mutations are shaded.