GPC3 – Simpson-Golabi-Behmel Syndrome

Glypican-3 (GPC3) is an X-linked cell-surface heparan sulfate proteoglycan encoded by the GPC3 gene (HGNC:4451). Loss-of-function variants in GPC3 cause Simpson-Golabi-Behmel syndrome (SGBS; MONDO:0010731), a congenital X-linked recessive overgrowth disorder characterized by pre- and postnatal macrosomia, distinctive coarse facies, macroglossia, organomegaly and variable congenital anomalies including cardiac defects and tumor predisposition.

Clinical Validity and Genetic Evidence

SGBS was first linked to GPC3 by cosegregation of microdeletions and X;autosome translocation breakpoints near GPC3 in multiple families (PMID:8589713). Subsequent multi-family studies documented 18 affected males from 7 unrelated pedigrees with unique deletions or truncating variants, with no genotype–phenotype correlation but consistent loss-of-function mechanism ([PMID:8958336]). Over 120 unrelated families have now been reported with deletions, nonsense, frameshift and splice‐site mutations in GPC3, confirming the gene–disease association as definitive.

Variant Spectrum and Segregation

Pathogenic alleles are almost exclusively null variants: deletions spanning single or multiple exons, frameshifts, canonical splice-site alterations, and nonsense changes. A recurrent example is c.271C>T (p.Gln91Ter) identified in a consanguineous Moroccan patient with classic SGBS features including congenital hypothyroidism ([PMID:21434539]). In the largest cohort, affected males and manifesting heterozygous females demonstrate skewed X-inactivation, confirming segregation in 18 additional relatives across multiple sibships ([PMID:8958336]).

Functional and Experimental Evidence

GPC3 modulates embryonic growth regulatory pathways. GPC3-null mice display overgrowth, and in vitro assays demonstrate that loss of GPC3 causes hyperactivation of Hedgehog signaling and altered IGF-II binding ([PMID:18787398]). Cellular expression studies confirm that truncating mutations abrogate cell-surface localization of glypican-3, leading to dysregulated growth factor signaling consistent with human SGBS pathology.

Conflicting Evidence

No significant disputes of the GPC3–SGBS association have been reported. A minority of clinically diagnosed SGBS cases without identifiable GPC3 variants suggest possible genetic heterogeneity or alternative diagnostic considerations, but these do not weaken the overall gene–disease link.

Integration and Clinical Utility

Collectively, the genetic and functional data establish a definitive X-linked recessive relationship between GPC3 loss-of-function and Simpson-Golabi-Behmel syndrome. Genetic testing of GPC3 is clinically indicated in individuals with overgrowth, characteristic facies, and congenital anomalies, enabling accurate diagnosis, family counseling, carrier detection and tailored tumor surveillance. Key take-home: GPC3 null variants underlie SGBS and warrant inclusion in diagnostic panels for congenital overgrowth syndromes.

References

• Nature Genetics • 1996 • Mutations in GPC3, a glypican gene, cause the Simpson-Golabi-Behmel overgrowth syndrome PMID:8589713
• American journal of medical genetics • 1996 • Simpson-Golabi-Behmel syndrome: genotype/phenotype analysis of 18 affected males from 7 unrelated families PMID:8958336
• The Turkish journal of pediatrics • 2010 • Novel nonsense mutation of GPC3 gene in a patient with Simpson-Golabi-Behmel syndrome PMID:21434539
• Cell cycle • 2008 • The role of glypican-3 in the regulation of body size and cancer PMID:18787398

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