Cantú Syndrome Is Caused by Mutations in ABCC9

• DOI: 10.1016/j.ajhg.2012.04.014
• Publication Date: 2012-05-17T15:15:31Z
• Authors: Bregje W.M. van Bon; Christian Gilissen; Dorothy K. Grange; Raoul C.M. Hennekam; Hülya Kayserili; Hartmut Engels; Heiko Reutter; John R. Ostergaard; Eva Morava; Konstantinos Tsiakas; Bertrand Isidor; Martine Le Merrer; Metin Eser; Nienke Wieskamp; Petra de Vries; Marloes Steehouwer; Joris A. Veltman; Stephen P. Robertson; Han G. Brunner; Bert B.A. de Vries; Alexander Hoischen
• Keywords: Adult; Male; Potassium Channels; Adolescent; Receptors, Drug; NCMLS 6: Genetics and epigenetic pathways of disease IGMD 3: Genomic disorders and inherited multi-system disorders; Molecular Sequence Data; Hypertrichosis; Cardiomegaly; Osteochondrodysplasias; Cohort Studies; 03 medical and health sciences; Genetics; Humans; Genetics(clinical); Potassium Channels, Inwardly Rectifying; IGMD 3: Genomic disorders and inherited multi-system disorders DCN MP - Plasticity and memory; Child; Genes, Dominant; 0303 health sciences; IGMD 4: Glycostation disorders; Base Sequence; Facies; Infant; Genetic Diseases, X-Linked; Sequence Analysis, DNA; 3. Good health; Laboratory Medicine - Radboud University Medical Center; Phenotype; Mutation; ATP-Binding Cassette Transporters; Female

Cantú syndrome is a rare disorder characterized by congenital hypertrichosis, neonatal macrosomia, a distinct osteochondrodysplasia, and cardiomegaly. Using an exome-sequencing approach applied to one proband-parent trio and three unrelated single cases, we identified heterozygous mutations in ABCC9 in all probands. With the inclusion of the remaining cohort of ten individuals with Cantú syndrome, a total of eleven mutations in ABCC9 were found. The de novo occurrence in all six simplex cases in our cohort substantiates the presence of a dominant disease mechanism. All mutations were missense, and several mutations affect Arg1154. This mutation hot spot lies within the second type 1 transmembrane region of this ATP-binding cassette transporter protein, which may suggest an activating mutation. ABCC9 encodes the sulfonylurea receptor (SUR) that forms ATP-sensitive potassium channels (K(ATP) channels) originally shown in cardiac, skeletal, and smooth muscle. Previously, loss-of-function mutations in this gene have been associated with idiopathic dilated cardiomyopathy type 10 (CMD10). These findings identify the genetic basis of Cantú syndrome and suggest that this is a new member of the potassium channelopathies.