PIGY – Congenital Disorder of Glycosylation

The PIGY gene is implicated in a congenital disorder of glycosylation characterized by a variable phenotype including seizures, cataracts, and microcephaly. Two independent families have been reported with homozygous recessive mutations in PIGY, establishing the clinical relevance of this gene to the disorder (PMID:26293662).

In the first family, two sisters presented with multisystem disease including severe developmental delay, dysmorphism, seizures, and cataracts. In the second family, two siblings exhibited moderate developmental delay and microcephaly. The presence of affected siblings in both families provides robust segregation evidence for the pathogenic role of the variants (PMID:26293662).

Genetic evidence is centered on the recurrent coding mutation c.137T>C (p.Leu46Pro), which was detected in affected individuals across the families. This variant was identified through whole exome sequencing and is supported by data indicating that homozygous recessive mutations in PIGY can lead to defective GPI-anchor biosynthesis (PMID:26293662).

Functional studies further substantiate the gene-disease association. Patient-derived skin fibroblasts demonstrated significantly reduced levels of GPI-anchored proteins (approximately 20–50% of control levels), and a separate analysis of a promoter variant (c.-54>A) indicated disrupted SP1 binding with consequent decreased gene expression. These findings corroborate the pathogenic mechanism linking reduced PIGY function to the observed clinical phenotype (PMID:26293662).

Integrating both genetic and functional findings, the evidence consistently supports a pathogenic role for PIGY variants in congenital disorder of glycosylation. Although the total number of reported affected individuals is limited, the convergence of segregation data and in vitro functional assays elevates the confidence in this association.

Key Take‑home: The combined genetic and functional evidence confirms that mutations in PIGY, including the recurrent c.137T>C (p.Leu46Pro) variant, are clinically significant in diagnosing congenital disorders of glycosylation, underpinning their utility in both diagnostic decision‑making and potential commercial applications.

References

• Human molecular genetics • 2015 • Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies. PMID:26293662

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