Duplications of GPC3 and GPC4 genes in symptomatic female carriers of Simpson-Golabi-Behmel syndrome type 1

GPC3 and GPC4 are the only two genes in which mutations are known to cause Simpson-Golabi-Behmel syndrome type 1 (SGBS1). The majority of SGBS1 patients have point mutations or deletions in GPC3. Only one SGBS1 family has been reported with duplication of both GPC3 and GPC4. Although clinical presentation of SGBS1 in affected males is well defined, the phenotype in female carriers is less clear. In total, six female carriers with clinical expression of SGBS1 have been reported to date. In this study, we provide description of two families with rare duplications in both GPC3 and GPC4. These imbalances resulted in SGBS1 in males, while female carriers with skewed X-inactivation exhibited significant features of SGBS1 including congenital heart defect, hernias, intellectual disability and coarse facial features. In family 2, a SGBS diagnosis was not considered in the father until after the diagnosis had been first considered and made in the affected daughter.We emphasize on the importance of testing at risk females and careful examination of those who are found to be carriers of SGBS1. We also discuss and provide supportive evidence for the role of skewed X-inactivation in clinical expression of SGBS1 in female carriers.