Familial Simpson-Golabi-Behmel syndrome: studies of X-chromosome inactivation and clinical phenotypes in two female individuals with GPC3 mutations.

Simpson-Golabi-Behmel syndrome (SGBS) is an overgrowth/multiple congenital anomalies syndrome with an X-linked inheritance. Most cases of SGBS are attributed to mutations in the glypican 3-gene (GPC3), which is highly expressed in the mesodermal embryonic tissues and involves in a local growth regulation. Typical clinical features include pre/postnatal overgrowth, developmental delay, macrocephaly, characteristic facies with prominent eyes and macroglossia, diaphragmatic hernia, congenital heart defects, kidney anomalies, and skeletal anomalies. Obligate carrier females with GPC3 mutations are usually asymptomatic or with mild symptoms. It is thought that skewed X-inactivation is the underlining mechanism for the female patients to present with findings of SGBS. We identified three siblings with typical SGBS (two male and one female cases) and their mother with very mild symptoms in a family carrying c.256C>T (p.Arg86X) mutation in GPC3. X-inactivation studies on the androgen-receptor gene (AR) and the Fragile XE (FRAXE) gene were performed with blood, buccal swabs, and fibroblasts in the carrier females. The studies with blood showed moderately skewed X-inactivation with paternal X-chromosome being preferentially inactivated (71-80% inactivated) in the female patient with SGBS and no skewing was shown in the mother with very mild symptoms. The X-inactivation studies in the mother showed inactivation of the X-chromosome with the mutation by 57%. This suggests that loss of the functional GPC3 protein by 43% is closed to the threshold to develop the SGBS phenotype. Studies with buccal swabs and fibroblasts failed to show different X-inactivation patterns between the two female individuals.