Mosaic monosomy of a neocentric ring chromosome maps brachyphalangy and growth hormone deficiency to 13q31.1-13q32.3

Abstract

We describe a boy with moderate intellectual disability associated with distinctive hand malformations (hypoplastic and angel‐shaped middle phalanges) and partial growth hormone (GH) deficiency associated with mosaic deletion of 13q31.1‐13q32.3. The deleted segment was mapped to a 20‐Mb region bounded by BACs RP11‐1143C2 and RP11‐139C1, narrowing the previously described locus for hand malformations at this region and suggesting that a locus for GH deficiency is also present at this location. The deleted segment contains at least three candidate genes, glypican‐5, FARP1 and SOX21, that may be contributing to the phenotype in this boy. In a significant proportion (approximately 50%) of cells, the deleted region is present as a supernumerary ring chromosome stabilized by the formation of a neocentromere at 13q31‐q32, within a region with a known propensity for neocentromere formation. The ring chromosome appears to be prone to low‐level misdivision and loss in vitro which, in vivo, must be countered by selection for the balanced karyotype because the level of mosaicism has remained stable over 13 years.