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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2015-08

AUTHORS

Katja Stange, Claus-Eric Ott, Mareen Schmidt-von Kegler, Gabriele Gillesen-Kaesbach, Stefan Mundlos, Katarina Dathe, Petra Seemann

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. More... »

PAGES

419-425

Identifiers

URI

http://scigraph.springernature.com/pub.10.1038/jhg.2015.48

DOI

http://dx.doi.org/10.1038/jhg.2015.48

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1047415914

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/25994865


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