Simpson-Golabi-Behmel Syndrome via the GPC3 Gene

Simpson-Golabi-Behmel syndrome (SGBS, OMIM 312870) is characterized clinically by pre- and postnatal overgrowth, distinct craniofacial and skeletal findings, and variable mental retardation. Craniofacial findings include macrocephaly, down-slanting palpebral fissures, ocular hypertelorism, epicanthal folds, broad and flat nasal bridge with short nose, low-set and posteriorly rotated ears, and large mouth and tongue. Skeletal and limb abnormalities include postaxial polydactyly of hands, syndactyly of the second and third fingers and toes, short and webbed neck, fusion of vertebrae, and pectus excavatum. Language delay is common, and mental retardation varies from mild to severe, although individuals with normal intelligence have been reported. Structural CNS findings, including agenesis of the corpus callosum, Chiari malformation, and hydrocephalus, have been reported (Young et al. Ped Neurol 34:139-142, 2006). Other findings include cardiac conduction defects, supernumerary nipples, and increased risk of embryonal tumors (Li et al. Am J Med Genet 102:161-168, 2001). Female carriers may exhibit some features of SGBS, and skewed X-inactivation has been reported to correlate with clinical features in females (Yano et al. Clin Genet doi:10.1111, 2010).

Simpson-Golabi-Behmel syndrome is inherited as an X-linked recessive disorder with marked inter- and intrafamilial variable expression. Variants in the GPC3 gene (OMIM 300037) were found to cause SGBS (Pilia et al. Nat Genet 12:241-247, 1996) and, to date, are the only known cause of this disorder. Penetrance in males is thought to be complete (James et al. GeneReviews, 2006). Penetrance in female carriers is unknown, although carriers can manifest some clinical features (Golabi and Rosen Am J Med Genet 17:345-348, 1984; Rodriguez-Criado Am J Med Genet 138A:272-277, 2005). Nearly fifty GPC3 variants have been reported. The great majority of these variants are deletions of one or more exons. Other variant types include missense, nonsense, and splicing defects that presumably result in loss of function. Gonadal mosaicism has been documented for GPC3 variants (Pilia et al. 1996; Romanelli et al. Clin Genet 72:384-386, 2007).

Because most causative GPC3 variants are deletions of single or multiple exons, clinical sensitivity of GPC3 sequencing is expected to be low. For example, Li et al. (2001) failed to identify any individuals with point variants among a group of 45 patients. Seven patients in this study were found to have deletions. In another study, however, six individuals were found to have GPC3 point variants among a cohort of 25 patients (Veugelers et al. Hum Mol Genet 9:1321-1328, 2000). Of these 25 patients, ten had a clinical diagnosis of SGBS, and the remaining were diagnosed with other overgrowth syndromes or were classified as undiagnosed overgrowth.

This test provides full coverage of all coding exons of the GPC3 gene, plus ~10 bases of flanking noncoding DNA. We define full coverage as >20X NGS reads or Sanger sequencing.