REPORT Mutations in ROGDI Cause Kohlschu ¨tter-To ¨nz Syndrome Anna Schossig, 1,3,14 Nicole I. Wolf, 2,4,14 Christine Fischer, 3 Maria Fischer, 5 Gernot Stocker, 5 Stephan Pabinger, 5 Andreas Dander, 5 Bernhard Steiner, 6 Otmar To ¨nz, 6 Dieter Kotzot, 1 Edda Haberlandt, 7 Albert Amberger, 1 Barbara Burwinkel, 8,9 Katharina Wimmer, 1 Christine Fauth, 1 Caspar Grond-Ginsbach, 10 Martin J. Koch, 11 Annette Deichmann, 12 Christof von Kalle, 12 Claus R. Bartram, 3 Alfried Kohlschu ¨tter, 13 Zlatko Trajanoski, 5 and Johannes Zschocke 1,3, * Kohlschu ¨tter-To ¨nz syndrome (KTS) is an autosomal-recessive disease characterized by the combination of epilepsy, psychomotor regres- sion, and amelogenesis imperfecta. The molecular basis has not yet been elucidated. Here, we report that KTS is caused by mutations in ROGDI. Using a combination of autozygosity mapping and exome sequencing, we identified a homozygous frameshift deletion, c.229_230del (p.Leu77Alafs*64), in ROGDI in two affected individuals from a consanguineous family. Molecular studies in two addi- tional KTS-affected individuals from two unrelated Austrian and Swiss families revealed homozygosity for nonsense mutation c.286C>T (p.Gln96*) and compound heterozygosity for the splice-site mutations c.531þ5G>C and c.532-2A>T in ROGDI, respectively. The latter mutation was also found to be heterozygous in the mother of the Swiss affected individual in whom KTS was reported for the first time in 1974. ROGDI is highly expressed throughout the brain and other organs, but its function is largely unknown. Possible interactions with DISC1, a protein involved in diverse cytoskeletal functions, have been suggested. Our finding that ROGDI mutations cause KTS indicates that the protein product of this gene plays an important role in neuronal development as well as amelogenesis. Kohlschu ¨tter-To ¨nz syndrome (KTS, MIM 226750) is a rare genetic disorder characterized by the combination of epilepsy, psychomotor delay and regression, and amelogen- esis imperfecta. So far, 24 individuals with the clinical diag- nosis of KTS have been reported. 1–9 Pedigrees suggest an autosomal-recessive mode of inheritance, but genetic heterogeneity cannot be excluded. The molecular basis of KTS has not yet been elucidated. The most striking feature is global enamel deficiency (amelogenesis imperfecta) of the hypoplastic or hypocalcified type; this deficiency affects primary as well as permanent teeth right from the moment of eruption. The enamel is very thin, rough, prone to disinte- gration, and stained in various shades of brown. Onset of epilepsy usually occurs in the first year of life; seizures are difficult to treat or might be refractory to therapy. Affected children show severe psychomotor delay or regression, which might be present after birth but more frequently develops after the onset of seizures. Both gross and fine motor skills are usually impaired, and intellectual disability might be severe. The natural course is variable; several affected individuals developed spastic tetraplegia, and some died in childhood. There are no consistent dysmorphic features or metabolic abnormalities, although nonspecific facial anomalies have been reported in some affected individ- uals. Cranial imaging frequently shows mild brain atrophy. In order to identify the genetic basis of KTS, we investi- gated four affected children from three families as well as healthy members of the index family reported in 1974. 1 Clinical features of the affected individuals are summa- rized in Table 1. Family A is a consanguineous Moroccan family with two affected children (A-IV:3 and A-IV:4; Figure 1); 9 the parents are first cousins. Initial development of the affected boy (A-IV:3) appeared normal, but treat- ment-resistant epilepsy started when he was 4 months old and led to loss of fixation and global developmental delay. The affected younger sister (A-IV:4) showed psycho- motor delay from birth onward. Epileptic seizures, which were difficult to treat, started when she was 12 months old. The first teeth in both children erupted when they were 13 and 14 months old, respectively; from the begin- ning, their teeth were lusterless and had a brownish dis- coloration. Family B has been reported previously; 8 the parents of the affected boy (B-II:1) are not knowingly related but come from neighboring villages in East Tyrol (Austria). Epilepsy started when the boy was 5 months old but later improved; there were no seizures after 7 years of age, and medication was discontinued when he was 15 years old. Primary and permanent teeth were yellow, hypoplastic, and crowded. Family C has one affected girl (C-XI:2) who has not yet been reported. Left-sided hemi- convulsive seizures started when she was 6 months old and were initially difficult to treat, but when she was 6 years old, anticonvulsive treatment could be discontin- ued. Primary and secondary dentition showed enamel 1 Division of Human Genetics, Medical University Innsbruck, 6020 Innsbruck, Austria; 2 Department of Child Neurology, VU University Medical Center, 1007 MB Amsterdam, The Netherlands; 3 Institute of Human Genetics, Heidelberg University, 69120 Heidelberg, Germany; 4 Department of Child Neurology, Heidelberg University, 69120 Heidelberg, Germany; 5 Division of Bioinformatics, Medical University Innsbruck, 6020 Innsbruck, Austria; 6 Chil- dren’s Hospital, 6000 Lucerne, Switzerland; 7 Department of Pediatrics, Medical University Innsbruck, 6020 Innsbruck, Austria; 8 German Cancer Research Center, 69120 Heidelberg, Germany; 9 Department of Obstetrics and Gynecology, Heidelberg University, 69120 Heidelberg, Germany; 10 Department of Neurology, Heidelberg University, 69120 Heidelberg, Germany; 11 Department of Oral, Dental, and Maxillofacial Diseases, Heidelberg University, 69120 Heidelberg, Germany; 12 National Center for Tumor Diseases and German Cancer Research Center, 69120 Heidelberg, Germany; 13 University Hospital for Child and Adolescent Medicine, 20246 Hamburg, Germany 14 These authors contributed equally to this work *Correspondence: johannes.zschocke@i-med.ac.at DOI 10.1016/j.ajhg.2012.02.012. Ó2012 by The American Society of Human Genetics. All rights reserved. The American Journal of Human Genetics 90, 701–707, April 6, 2012 701