PIGS – Congenital Disorder of Glycosylation

This summary outlines the association between PIGS and congenital disorder of glycosylation. Multiple independent studies have shown that biallelic, typically compound heterozygous and occasionally homozygous, variants in PIGS are consistently observed in patients presenting with a spectrum of neurological and developmental abnormalities. The overall evidence supporting this association is classified as Strong based on ClinGen criteria, with robust clinical, segregation, and functional data reported across diverse populations (PMID:32612635, PMID:33410539, PMID:30269814).

Patients with PIGS‐associated disorders exhibit a complex phenotype that includes hypotonia, infantile spasms, hearing impairment, severe global developmental delay, visual impairment, intellectual disability, abnormal renal morphology, microcephaly, ataxia, seizures, and abnormal facial shape. These overlapping features have been documented in case reports and multi‐patient series, highlighting the multisystemic effects of GPI‑anchor biosynthesis disruption. The convergence of these clinical findings across independent studies reinforces the significant impact of PIGS variants on neurodevelopment and systemic function.

The genetic evidence is compelling with an autosomal recessive inheritance pattern. In the reported cases, affected individuals harbor compound heterozygous or homozygous variants, including the recurrent variant c.1141_1164dup (p.Asp381_Val388dup), which was observed in both the case report and one of the multi‐patient studies. This variant, among others, exemplifies the spectrum of coding changes in PIGS that lead to a loss of normal protein function and underpins the molecular diagnosis of this congenital disorder (PMID:32612635, PMID:33410539).

Segregation analysis, while variably reported, has confirmed the co‐segregation of the pathogenic variants with the disease phenotype in affected family members. In at least one family, additional affected relatives (e.g., siblings) were identified as carrying the same biallelic variants, thereby reinforcing the genetic causality of the association. This intra‑familial consistency adds weight to the overall genetic evidence behind the disorder.

Functional studies have further contributed to our understanding of the disease mechanism by demonstrating that patients with PIGS variants show a significant reduction in the cell surface expression of glycosylphosphatidylinositol‑anchored proteins. Flow cytometry assays performed on patient‐derived samples consistently displayed decreased GPI‑AP expression, which is in line with a pathogenic model of GPI deficiency. These results provide moderate functional evidence, substantiating the link between the genetic defect and the clinical phenotype (PMID:32612635).

In conclusion, the integration of robust genetic evidence, clear clinical presentation, and supportive functional data establishes a Strong association between PIGS and congenital disorder of glycosylation. The convergence of data from independent studies across diverse populations enhances the clinical utility of this finding, underscoring the importance of including PIGS in diagnostic genetic testing panels for pediatric neurodevelopmental disorders. Key take‑home: Recognizing PIGS‐associated pathology can enable timely diagnosis and informed therapeutic decision‑making.

References

• Frontiers in Genetics • 2020 • Compound Heterozygous PIGS Variants Associated With Infantile Spasm, Global Developmental Delay, Hearing Loss, Visual Impairment, and Hypotonia PMID:32612635
• Epilepsia • 2021 • Expanding the Phenotype of PIGS‑Associated Early Onset Epileptic Developmental Encephalopathy PMID:33410539
• American Journal of Human Genetics • 2018 • Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy PMID:30269814

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