Nadja Ehmke, Almuth Caliebe, Rainer Koenig, Sarina G

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Homozygous and Compound-Heterozygous Mutations in TGDS Cause Catel-Manzke Syndrome Nadja Ehmke, Almuth Caliebe, Rainer Koenig, Sarina G. Kant, Zornitza Stark, Valérie Cormier-Daire, Dagmar Wieczorek, Gabriele Gillessen-Kaesbach, Kirstin Hoff, Amit Kawalia, Holger Thiele, Janine Altmüller, Björn Fischer-Zirnsak, Alexej Knaus, Na Zhu, Verena Heinrich, Celine Huber, Izabela Harabula, Malte Spielmann, Denise Horn, Uwe Kornak, Jochen Hecht, Peter M. Krawitz, Peter Nürnberg, Reiner Siebert, Hermann Manzke, Stefan Mundlos The American Journal of Human Genetics Volume 95, Issue 6, Pages 763-770 (December 2014) DOI: 10.1016/j.ajhg.2014.11.004 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Clinical Features of Individuals 1 and 7 (A and B) Clinical photographs of individual 1 performed at the age of 6 days showing severe micrognathia, a short neck, and low set and dysplastic ears. (C and D) Hand radiographs of individual 1 at the age of 6 days showing the Manzke dysostosis. (E and F) Hand radiographs of individual 7 performed at the age of 28 years showing bilateral radial deviation and clinodactyly of the second digit. On the right hand a triangular-shaped bone is inserted between the second metacarpal and its proximal phalanx, and on the left hand the accessory bone and proximal phalanx fused. The American Journal of Human Genetics 2014 95, 763-770DOI: (10.1016/j.ajhg.2014.11.004) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Clinical Features of Individual 2 (A–C) Clinical photographs of individual 2 performed at the age of 5 months showing micrognathia, upslanting palpebral fissures, short nose with anteverted nares, thin eyebrows, and cleft palate. (D and F) Clinical photographs of both hands of individual 2 showing the clinodactyly of the index fingers, which is more pronounced on the left side. (E and G) Hand radiographs of individual 2 performed at the age of 3 months showing a triangular-shaped bone inserted between the second metacarpal and its proximal phalanx bilaterally causing radial deviation of the index finger. On the left hand an additional pin-shaped ossification center is visible. The American Journal of Human Genetics 2014 95, 763-770DOI: (10.1016/j.ajhg.2014.11.004) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Segregation Analysis of the TGDS Variants and Predicted Effects on the Protein (A) Pedigree structures and TGDS genotypes for the seven families. (B) Schematic of human TGDS showing the predicted domains, the position of the amino acid changes, and the conservation. RefSeq accession numbers are as follows: human, NM_014305.2; mouse, NP_083854; zebrafish, AAH_66615; E. coli, WP_001710460; C. elegans, NP_508390. The predicted domains are based on the Conserved Domain Database. The triangles show conserved positions. The alignment was created with BoxShade and ClustalW. The colored background of the aa in the different species indicates the degree of conservation (black, conserved; gray, similarity in properties; white, not conserved, no similarity in properties). (C) Predicted position of the amino acid changes in the structure of TGDS in Pyrococcus horikoshii. The structure of TGDS is shown as a model created with PyMol. The substrate binding domain is shown in blue, and the NAD binding domain is in light green. The positions aligning with the amino acid changes in TGDS in our cohort are framed in magenta. Ala100 and Phe98 are localized in the NAD-binding domain, and Asn298 is in the substrate binding domain. Glu90 and Tyr234 are localized in two of the loops. The American Journal of Human Genetics 2014 95, 763-770DOI: (10.1016/j.ajhg.2014.11.004) Copyright © 2014 The American Society of Human Genetics Terms and Conditions