Further delineation of the GDF6 related multiple synostoses syndrome

Abstract

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.

A Novel GDF6 Mutation in a Family with Multiple Synostoses Syndrome without Hearing Loss

“…3 a), in line with the notion that SYNS4 is caused by gain-of-function mutations making GDF6 noggin resistant [Wang et al, 2016;Terhal et al, 2018]. When comparing the carpal and tarsal synostoses in our patients to the 2 previously reported families, 1 Dutch and 1 Chinese [Wang et al, 2016;Terhal et al, 2018], the skeletal phenotype is highly similar. Synostoses in fingers, knees, elbows, or vertebrae have not been reported, which makes SYNS4 different from SYNS1, SYNS2, and SYNS3.…”

“…The skeletal phenotype of symmetrical carpal and tarsal synostoses is similar to the skeletal phenotype found in the 2 previous families [Wang et al, 2016;Terhal et al, 2018]. However, unlike these families, none of the 9 affected individuals in our family have mechanical hearing loss, and we speculate that this may be related to GDF6-N399K having no effect on receptor dimerization.…”

“…In the Chinese family [Wang et al, 2016], some of the patients had progressive conductive hearing loss after age 40, and in the Dutch family [Terhal et al, 2018], at least 6 of 10 patients had hearing loss, and severe stapes fixation was detected as early as age 6 years. Although we cannot completely rule out late-onset otosclerosis in our family, this seems unlikely as audiometric testing in individual II-3 at 73 years of age was not indicative of otosclerosis, and other affected family members (including II-1 and III-1) are reported to hear well.…”

“…Just as GDF5, GDF6 is a secreted growth factor of the BMP family that plays an important role in joint formation [Settle et al, 2003]. Since increased BMP signaling of various causes is associated with other multiple synostoses syndromes, noggin resistance of mutant GDF6s is postulated to be the major cause of SYNS4 [Wang et al, 2016;Terhal et al, 2018]. Other missense mutations in GDF6 have been reported in Klippel-Feil syndrome type 1, Leber congenital amaurosis type 17, and isolated microphthalmia [Tassabehji et al, 2008;Asai-Coakwell et al, 2009], but since several of these missense mutations are frequently found in normal control populations, their contribution to the etiology of these conditions is doubtful [Terhal et al, 2018].…”

“…SYNS4 is caused by gain-of-function mutations in GDF6 , encoding growth/differentiation factor 6 [Wang et al, 2016;Terhal et al, 2018]. The SYNS4 phenotype comprises variable carpal and tarsal synostoses, and some patients have otosclerosis and conductive hearing loss.…”