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Kohlschütter–Tönz Syndrome: Mutations in ROGDI and Evidence of Genetic Heterogeneity


  • Communicated by Lars Bertman

  • Contract grant sponsor: Intramural Research Program of the National Institute on Aging, National Institutes of Health, Department of Health and Human Services (Z01 AG 000958–08).

Correspondence to: Johannes Zschocke, Division of Human Genetics, Medical University Innsbruck, Schöpfstr. 41, Innsbruck 6020, Austria. E-mail:; Henry Houlden, Department of Molecular Neuroscience, Institute of Neurology, University College London, Queen Square WC1N 3BG, London, UK. E-mail:


Kohlschütter–Tönz syndrome (KTS) is a rare autosomal recessive disorder characterized by amelogenesis imperfecta, psychomotor delay or regression and seizures starting early in childhood. KTS was established as a distinct clinical entity after the first report by Kohlschütter in 1974, and to date, only a total of 20 pedigrees have been reported. The genetic etiology of KTS remained elusive until recently when mutations in ROGDI were independently identified in three unrelated families and in five likely related Druze families. Herein, we report a clinical and genetic study of 10 KTS families. By using a combination of whole exome sequencing, linkage analysis, and Sanger sequencing, we identify novel homozygous or compound heterozygous ROGDI mutations in five families, all presenting with a typical KTS phenotype. The other families, mostly presenting with additional atypical features, were negative for ROGDI mutations, suggesting genetic heterogeneity of atypical forms of the disease.