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  Brachydactyly Type C patient with compound heterozygosity for p.Gly319Val and p.Ile358Thr variants in the GDF5 proregion: benign variants or mutations?

Stange, K., Ott, C. E., Schmidt-von Kegler, M., Gillesen-Kaesbach, G., Mundlos, S., Dathe, K., et al. (2015). Brachydactyly Type C patient with compound heterozygosity for p.Gly319Val and p.Ile358Thr variants in the GDF5 proregion: benign variants or mutations? JOURNAL OF HUMAN GENETICS, 60(8), 419-425. doi:10.1038/jhg.2015.48.

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Item Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-60A8-A Version Permalink: http://hdl.handle.net/11858/00-001M-0000-002A-60A9-8
Genre: Journal Article

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© 2015 The Japan Society of Human Genetics
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 Creators:
Stange, K.1, Author
Ott, C. E.2, Author
Schmidt-von Kegler, M.1, Author
Gillesen-Kaesbach, G., Author
Mundlos, S.1, 2, 3, Author              
Dathe, K.2, Author
Seemann, P.1, Author
Affiliations:
1Berlin Brandenburg Center for Regenerative Therapies (BCRT), Charité–Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
2Institute for Medical Genetics and Human Genetics, Charité–Universitätsmedizin Berlin, Berlin, Germany, ou_persistent22              
3Research Group Development & Disease (Head: Stefan Mundlos), Max Planck Institute for Molecular Genetics, Max Planck Society, ou_1433557              

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 Abstract: We report on a Brachydactyly Type C (BDC) patient with clinically inconspicuous parents. Molecular genetic analyses revealed compound heterozygosity for two GDF5 variants. The variant c.956G>T (p.Gly319Val) was inherited from her mother and has been reported in exome sequencing projects, whereas c.1073T>C (p.Ile358Thr) has never been reported so far. In silico, both variants were predicted to be 'disease-causing', but the fact that p.Ile358Thr was predicted by SIFT to be 'tolerated' raised our suspicion. Therefore, we performed in vitro assays. To our surprise, GDF5(G319V) showed pronounced loss of function in luciferase reporter assays and in vitro chondrogenesis, whereas GDF5(I358T) and GDF5(WT) had comparable biological activities. Western blot analyses revealed decreased protein levels after overexpression of GDF5(G319V). In absence of linkage or de novo mutation, several scenarios could explain the underlying mechanism of the patient's phenotype. Owing to reduced activity of GDF5(G319V) in our functional assays, p.Gly319Val might be causative for BDC, but typically evoke an unrecognizably mild phenotype or even nonpenetrance. Another possibility is that our assays failed to pinpoint the disease-causing mechanism of the p.Ile358Thr allele. A final possibility is that compound heterozygosity for p.Ile358Thr and p.Gly319Val is more deleterious to GDF5 activity than either variant alone. Until all possible explanations can be rigorously tested experimentally, a precise recurrence risk counseling for the parents and the affected child is not possible.

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Language(s): eng - English
 Dates: 2015-05-212015-08
 Publication Status: Published in print
 Pages: 7
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 Table of Contents: -
 Rev. Type: -
 Identifiers: DOI: 10.1038/jhg.2015.48
ISSN: 1435-232X (Electronic)1434-5161 (Print)
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Title: JOURNAL OF HUMAN GENETICS
  Other : J. Hum. Genet.
Source Genre: Journal
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Publ. Info: Tokyo : Springer-Verlag
Pages: - Volume / Issue: 60 (8) Sequence Number: - Start / End Page: 419 - 425 Identifier: ISSN: 1434-5161
CoNE: https://pure.mpg.de/cone/journals/resource/954926986106