Molecular Genetics of Simpson‐Golabi‐Behmel Syndrome Type 1

AbstractSimpson‐Golabi‐Behmel syndrome (SGBS; OMIM #312870) is a recessive X‐linked overgrowth disorder manifesting multiple congenital anomalies and visceral and skeletal abnormalities. It is caused by deletions or duplications of the heparan sulfate proteoglycan glypican 3‐gene (GPC3; OMIM #30037) and/or duplication of the glypican 4‐gene (GPC4; OMIM #300168) at Xq26. Heparan sulfate proteoglycans mechanism of GPC3 and GPC4 in producing the SGBS phenotype is poorly understood and SGBS is suspected to be under‐reported. Suspected SGBS individuals should be tested for GPC3 mutations or deletion and GPC4 duplication. Current literature states no correlation between deletion size and phenotype for SGBS. Future investigative studies are recommended to define genotype–phenotype correlation and understand the GPC3/GPC4 gene‐product mechanism.Key Concepts:GPC3 and GPC4 lay tandem in sequence within the Xq26 locus.The glypican‐3 protein mediates embryonic and cell‐specific tissue formation and development by regulating growth factors.Point mutations or microdeletions in GPC3 or duplication of GPC4 result in a premature termination codon and will be translated to a truncated protein or nonfunctional glypican‐3 or glypican‐4 protein.Loss‐of‐function mutation in GPC3 is associated with SGBS but further studies on GPC4 are necessary to define its association with SGBS.Current literature states no correlation between deletion size and phenotype for SGBS.