A mutation in GDF6 was recently found to underlie a multiple synostoses syndrome. In this report, we describe the second family with GDF6-related multiple synostoses syndrome (SYNS4), caused by a novel c.1287C>A/p.Ser429Arg mutation in GDF6. In addition to synostoses of carpal and/or tarsal bones, at least 6 of 10 affected patients in this family have been diagnosed with mild to moderate hearing loss. In four of them otosclerosis was said to be present, one patient had hearing loss due to severe stapes fixation at the age of 6 years, providing evidence that hearing loss in the GDF6-related multiple synostoses syndrome can be present in childhood. Two others had surgery for stapes fixation at adult age. We hypothesize that, identical to the recently published GDF6-related multiple synostoses family, the p.Ser429Arg mutation also leads to a gain of function. The previously reported c.1330T>A/pTyr444Asn mutation was located in a predicted Noggin and receptor I interacting domain and the gain of function was partly due to resistance of the mutant GDF6 to the BMP-inhibitor Noggin. The results in our family show that mutations predicting to affect the type II receptor interface can lead to a similar phenotype and that otosclerosis presenting in childhood can be part of the GDF6-related multiple synostoses syndrome.

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Keywords BMP/TGFß signaling, GDF6, Multiple synostoses, Noggin, Tarsal-carpal fusion
Persistent URL dx.doi.org/10.1002/ajmg.a.38503, hdl.handle.net/1765/102910
Journal American Journal of Medical Genetics. Part A
Terhal, P, Verbeek, N.E, Knoers, N.V.A.M, Nievelstein, R.J.A.J. (Rutger J. A. J.), van den Ouweland, A.M.W, Sakkers, R.J. (Ralph J.), … van Haaften, G. (2017). Further delineation of the GDF6 related multiple synostoses syndrome. American Journal of Medical Genetics. Part A. doi:10.1002/ajmg.a.38503