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Simpson-Golabi-Behmel syndrome type 1 (SGBS1) is a rare X-linked recessive overgrowth disorder characterized by pre- and postnatal macrosomia, coarse facial features, supernumerary nipples, congenital anomalies (e.g., polydactyly, diaphragmatic hernia), and an increased risk of embryonal tumors. Loss-of-function variants in GPC3 are the primary cause of SGBS1, with multiple reports of point mutations, frameshifts, nonsense mutations, exon deletions, and genomic rearrangements disrupting glypican-3 expression ([PMID:22807161]; [PMID:10814714]).
Genetic evidence supporting a definitive association includes over 120 unrelated SGBS1 families harboring GPC3 mutations, with 86 distinct pathogenic variants reported in 120 families worldwide ([PMID:29637653]; [PMID:23463737]). Additional case series and prenatal studies have described at least 10 more probands with novel truncating or missense variants (e.g., one case with c.1692delT (p.Leu565SerfsTer63)) ([PMID:26321508]; [PMID:36720533]; [PMID:27589329]). Segregation analysis in multiple pedigrees demonstrates co-segregation of GPC3 variants with disease, including six symptomatic female carriers exhibiting skewed X-inactivation ([PMID:30048822]).
The variant spectrum is dominated by loss-of-function alleles: frameshift (e.g., c.1692delT (p.Leu565SerfsTer63)), nonsense (e.g., c.1515C>A (p.Cys505Ter)), splice-site, and multi-exon deletions or duplications. Rare missense variants have been functionally characterized and shown to impair proteolytic processing or cell-surface localization (e.g., p.Trp296Arg) ([PMID:10814714]). Founder or recurrent alleles have not been widely reported, indicating a diverse mutational landscape.
Functional studies demonstrate that glypican-3 deficiency leads to hyperactivation of Hedgehog signaling in cell and mouse models, recapitulating the overgrowth phenotype observed in SGBS1 ([PMID:18787398]). Placental immunohistochemistry shows a reproducible “null” staining pattern in affected individuals, providing a rapid prenatal diagnostic adjunct ([PMID:35796063]). These data confirm a loss-of-function mechanism for GPC3 variants in SGBS1 pathogenesis.
No reports have refuted the GPC3–SGBS1 association. Observations of GPC3 silencing in ovarian cancer cell lines reflect tumor-specific methylation and do not undermine its causative role in neonatal overgrowth syndromes ([PMID:10029067]).
In summary, the GPC3–SGBS1 relationship meets criteria for a Definitive gene–disease association, supported by extensive genetic and experimental evidence across large cohorts and functional models. Clinical genetic testing of GPC3 should be considered in fetuses and neonates with unexplained overgrowth and characteristic anomalies. Key take-home: GPC3 loss-of-function variants are a definitive cause of Simpson-Golabi-Behmel syndrome type 1, and combined molecular and histopathological assays enable early and accurate diagnosis.
Gene–Disease AssociationDefinitiveOver 120 unrelated SGBS1 families with GPC3 mutations across >20 years; extensive segregation and concordant functional data Genetic EvidenceStrong86 distinct variants in 120 probands; multiple case series and familial segregation Functional EvidenceStrongCell and mouse models recapitulate overgrowth via Hedgehog hyperactivation; placental IHC provides predictive phenotype |