A homozygous mutation in Smoothened, a member of the Sonic Hedgehog (SHH)-GLI pathway is involved in human syndromic atrioventricular septal defect. W. S. Kerstjens-Frederikse1, Y. Sribudiani2, M. E. Baardman1, L. M. A. Van Unen2, R. Brouwer2, M. van den Hout2, C. Kockx2, W. Van IJcken2, A. J. Van Essen1, P. A. Van Der Zwaag1, G. J. Du Marchie Sarvaas3, R. M. F. Berger3, F. W. Verheijen2, R. M. W. Hofstra2 1) Dept Gen, Univ of Groningen, Univ Med Ctr Groningen, Netherlands; 2) Dept Gen, Erasmus Med Ctr, Rotterdam, Netherlands; 3) Dept Ped Cardiol, Univ of Groningen, Univ Med Ctr Groningen, Netherlands.

   Introduction: Atrioventricular septal defect (AVSD) is a common congenital heart disease with a high impact on personal health. It is often accompanied by other congenital anomalies and in many of these syndromic AVSDs, defects in the sonic hedgehog (SHH)-GLI signalling pathway have been detected. SMO codes for the transmembrane protein smoothened (SMO), which is active in cells with a primary cilium and is located on the ciliary membrane. SMO is a key protein in the SHH-GLI signaling cascade. Methods: Two probands, a twin boy and girl, presented with an AVSD, large fontanel, postaxial polydactyly and skin syndactyly of the second and third toes of both feet. The boy also had hypospadias. The parents were consanguineous and they had one healthy older child. Karyotyping was normal and Smith-Lemli-Opitz syndrome (SLOS) was excluded. Exome sequencing was performed and candidate variants were validated by Sanger sequencing. Results: A novel homozygous missense mutation c.1725C>T (p.R575W) in SMO (7q32.3) was detected. Functional studies in fibroblasts of the patients showed normal expression of SMO protein but an abnormal localization of SMO, outside the cilia. Moreover we show severely reduced downstream GLI1 mRNA expression after stimulation with the SMO agonist purmorphamine. These results, together with the previously described association of SHH signalling defects with AVSD and SLOS, suggest that this SMO mutation is involved in syndromic AVSD in these patients. Conclusion: We present the first reported smoothened mutation in humans, in two patients with an AVSD and a phenotype resembling Smith-Lemli-Opitz syndrome.

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