Homozygous and compound-heterozygous mutations in TGDS cause Catel-Manzke syndrome

Am J Hum Genet. 2014 Dec 4;95(6):763-70. doi: 10.1016/j.ajhg.2014.11.004.

Nadja Ehmke ¹, Almuth Caliebe ², Rainer Koenig ³, Sarina G Kant ⁴, Zornitza Stark ⁵, Valérie Cormier-Daire ⁶, Dagmar Wieczorek ⁷, Gabriele Gillessen-Kaesbach ⁸, Kirstin Hoff ⁹, Amit Kawalia ¹⁰, Holger Thiele ¹⁰, Janine Altmüller ¹¹, Björn Fischer-Zirnsak ¹², Alexej Knaus ¹², Na Zhu ¹³, Verena Heinrich ¹³, Celine Huber ⁶, Izabela Harabula ¹⁴, Malte Spielmann ¹², Denise Horn ¹³, Uwe Kornak ¹⁵, Jochen Hecht ¹⁵, Peter M Krawitz ¹⁵, Peter Nürnberg ¹⁶, Reiner Siebert ², Hermann Manzke ¹⁷, Stefan Mundlos ¹⁸

Affiliations

1 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany. Electronic address: [email protected].
2 Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany.
3 Institute of Human Genetics, Goethe-University Frankfurt, 60590 Frankfurt am Main, Germany.
4 Department of Clinical Genetics, Leiden University Medical Center, 2300 RC Leiden, the Netherlands.
5 Victorian Clinical Genetics Service, Murdoch Children's Research Institute, Parkville, VIC 3052, Australia.
6 Department of Genetics, INSERM UMR 1163, Université Paris Descartes-Sorbonne PARIS Cité, Imagine Institute, Hôpital Necker Enfants Males, 75015 Paris, France.
7 Institut für Humangenetik, Universitätsklinikum Essen, Universität Duisburg-Essen, 45122 Essen, Germany.
8 Institut für Humangenetik, Universität zu Lübeck, 23538 Lübeck, Germany.
9 Institute of Human Genetics, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; Department of Congenital Heart Disease and Pediatric Cardiology, Christian-Albrechts-University Kiel & University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany; DZHK (German Centre for Cardiovascular Research), partner site Hamburg/Kiel/Lübeck, 24105 Kiel, Germany.
10 Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany.
11 Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Institute of Human Genetics, University of Cologne, 50931 Cologne, Germany.
12 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
13 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany.
14 Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
15 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany.
16 Cologne Center for Genomics (CCG), University of Cologne, 50931 Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, 50931 Cologne, Germany; Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, 50931 Cologne, Germany.
17 Private, 24226 Heikendorf, Germany.
18 Institute of Medical and Human Genetics, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany; Max Planck Institute for Molecular Genetics, 14195 Berlin, Germany. Electronic address: [email protected].

PMID: 25480037 DOI: 10.1016/j.ajhg.2014.11.004

Abstract

Catel-Manzke syndrome is characterized by Pierre Robin sequence and a unique form of bilateral hyperphalangy causing a clinodactyly of the index finger. We describe the identification of homozygous and compound heterozygous mutations in TGDS in seven unrelated individuals with typical Catel-Manzke syndrome by exome sequencing. Six different TGDS mutations were detected: c.892A>G (p.Asn298Asp), c.270_271del (p.Lys91Asnfs(∗)22), c.298G>T (p.Ala100Ser), c.294T>G (p.Phe98Leu), c.269A>G (p.Glu90Gly), and c.700T>C (p.Tyr234His), all predicted to be disease causing. By using haplotype reconstruction we showed that the mutation c.298G>T is probably a founder mutation. Due to the spectrum of the amino acid changes, we suggest that loss of function in TGDS is the underlying mechanism of Catel-Manzke syndrome. TGDS (dTDP-D-glucose 4,6-dehydrogenase) is a conserved protein belonging to the SDR family and probably plays a role in nucleotide sugar metabolism.

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