PIGG – congenital disorder of glycosylation

This summary synthesizes evidence linking biallelic loss‐of‐function variants in PIGG to congenital disorder of glycosylation. Clinical investigations have revealed that affected individuals present with a consistent phenotype including intellectual disability, cerebellar hypoplasia, and ataxia. Detailed case reports and multi‑patient studies have confirmed the association via both genetic and functional assays, establishing reproducible findings across diverse cohorts (PMID:28581210, PMID:34113002).

Genetic evidence is robust, with at least 22 affected individuals from 19 unrelated families demonstrating a recessive pattern of inheritance. Notably, a recurrent null variant, c.1640G>A (p.Trp547Ter), has been identified in multiple cases and is supported by the presence of additional loss‐of‐function alleles. This genetic replication across families underpins the strong gene‑disease association and emphasizes the diagnostic value of sequencing PIGG in suspected congenital glycosylation disorders (PMID:28581210).

Segregation analyses in these studies indicate that affected siblings and other relatives consistently co‐segregate with the pathogenic alleles. These observations reinforce the autosomal recessive inheritance pattern, and the clustering of null variants lends further support to the loss‐of‐function mechanism as the basis for the disorder. The data overall fulfill key ClinGen criteria for a strong gene‑disease relationship (PMID:34113002).

Complementary functional assessments have provided biological plausibility to the genetic findings. In vitro studies involving patient fibroblasts demonstrated reduced levels of GPI anchors and specific GPI‑linked proteins, while a PIGG/PIGO double knockout system confirmed deleterious effects on enzyme activity. These results are concordant with the clinical phenotype and support an underlying mechanism of GPI deficiency contributing to the observed neurological deficits (PMID:28581210).

Integrating the genetic and functional data yields a coherent narrative where multiple loss‑of‑function variants in PIGG produce a consistent clinical syndrome. The convergence of evidence from segregation studies, recurrent deleterious alleles, and targeted functional experiments strongly supports the pathogenicity of these variants. It is noteworthy that while the cumulative evidence exceeds traditional ClinGen scoring caps, it remains directly applicable for diagnostic decision‑making and commercial assay development.

Key take‑home message: Comprehensive evaluation of PIGG mutations, particularly the recurrent c.1640G>A (p.Trp547Ter) variant, provides a reliable biomarker for congenital disorder of glycosylation, reinforcing its clinical utility in genetic diagnostics.

References

• Human Mutation • 2017 • Reduced cell surface levels of GPI‑linked markers in a new case with PIGG loss of function PMID:28581210
• Genetics in Medicine • 2021 • PIGG variant pathogenicity assessment reveals characteristic features within 19 families PMID:34113002

Evidence Based Scoring (AI generated)