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

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

Author information

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: nadja.ehmke@charite.de.
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: stefan.mundlos@charite.de.

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.

PMID:
25480037
PMCID:
PMC4259972
DOI:
10.1016/j.ajhg.2014.11.004
[Indexed for MEDLINE]
Free PMC Article

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