GPC4 – Keipert syndrome

Keipert syndrome is an X-linked recessive disorder characterized by distinctive craniofacial anomalies and digital abnormalities. Affected males present with prominent forehead, flat midface, hypertelorism, broad nose, downturned corners of the mouth, brachydactyly, and variable cognitive impairment (PMID:30982611). The causative gene, GPC4, encodes glypican-4, a heparan sulfate proteoglycan critical for growth-factor signaling during embryonic development.

Whole-exome sequencing in the index Australian family revealed a hemizygous truncating variant resulting in a protein truncated 51 amino acids upstream of the stop codon. Seven additional affected males from five unrelated kindreds harbored novel predicted loss-of-function variants, all segregating with disease in carrier females with skewed X-inactivation (PMID:30982611).

The allelic series includes at least four truncating or frameshift variants: c.316del (p.Asp106fs), c.701dup (p.Val235fs), c.1486G>T (p.Glu496Ter), and c.1516C>T (p.Gln506Ter) (PMID:30982611). A recent report identified c.1051C>T (p.Arg351Ter) in a 3-year-old boy presenting with lacrimal punctal agenesis and typical Keipert features, expanding the phenotypic and molecular spectrum (PMID:38923342). An intronic splice region change c.877+?A was also described in a two-year-old patient, establishing additional allelic heterogeneity (PMID:35168097).

Functional assays demonstrate that recombinant truncated glypican-4 proteins exhibit reduced stability relative to wild type, supporting a loss-of-function mechanism. Gpc4 knockout mice recapitulate the core craniofacial and digital phenotypes of Keipert syndrome, confirming experimental concordance with human disease (PMID:30982611).

Integration of multiple unrelated probands (8 total) with consistent segregation in 6 families, combined with in vitro and in vivo functional data, supports a Strong ClinGen classification for the GPC4–Keipert syndrome association. Key Take-home: Hemizygous loss-of-function variants in GPC4 are highly predictive of Keipert syndrome in affected males.

References

• American Journal of Human Genetics • 2019 • Pathogenic Variants in GPC4 Cause Keipert Syndrome. PMID:30982611
• American Journal of Medical Genetics. Part A • 2024 • GPC4 truncating variant associated with Keipert syndrome and lacrimal punctal agenesis. PMID:38923342
• Stem Cell Research • 2022 • Generation of an induced pluripotent stem cell line ATCi002-A from a two-year-old Chinese boy with Keipert syndrome. PMID:35168097

Evidence Based Scoring (AI generated)