PIGC and Intellectual Disability

The association between the PIGC gene (HGNC:8960) and intellectual disability (MONDO_0001071) has been demonstrated in multiple independent studies. Patients across these studies present with global developmental delay, severe intellectual disability, and seizures, suggesting that disruption of the glycosylphosphatidylinositol (GPI) anchor biosynthesis is central to the disease mechanism. Exome analyses in affected individuals from consanguineous families have identified both homozygous and compound heterozygous mutations. These findings are supported by robust segregation data within affected families, underscoring an autosomal recessive inheritance pattern. The consistency of the clinical phenotype across unrelated families reinforces the association of PIGC variants with the neurological disorder. Overall, the clinical and genetic data collectively emphasize the relevance of PIGC in neurodevelopment.

Detailed genetic evaluations revealed several variant types in the PIGC gene across independent cohorts. In one study, three patients from two unrelated families were reported, while another described two affected siblings from a consanguineous union. Among the reported changes, the variant c.635T>C (p.Leu212Pro) stands out as a representative pathogenic alteration. This variant, along with others of similar effect, has been confirmed in multiple families, with segregation analysis demonstrating that the variants co‐segregate with the disease phenotype (PMID:27694521, PMID:32707268). The presence of both missense and predicted truncating variants adds to the mutational heterogeneity. Such a spectrum of genetic findings contributes significantly to the overall evidence supporting the gene-disease association.

Functional studies have played a pivotal role in affirming the pathogenicity of PIGC variants. Experimental work involving transfection of PIGC-deficient mouse cells demonstrated a marked reduction in the surface expression of GPI-anchored proteins, a finding that was recapitulated in patients’ leukocytes. These assays indicate a loss-of-function mechanism, which is consistent with the observed clinical phenotype. The quantitative decrease in GPI-anchored markers, as measured by flow cytometry, strongly supports the deleterious impact of the identified mutations. This experimental concordance with the clinical picture further validates the role of PIGC in the etiology of intellectual disability. Together, the functional data provide an essential bridge between molecular aberrations and the resultant neurological impairments.

Segregation evidence further compounds the strength of the genetic findings. In one family, two affected siblings were found to harbor the same homozygous mutation, while compound heterozygous mutations were observed in another family. The co-segregation of these variants with the disease phenotype across families confirms autosomal recessive inheritance. A cumulative total of approximately five probands across these studies (three in one study and two in another) have been detailed, which, despite being modest in number, is reinforced by comprehensive segregation and functional data (PMID:27694521, PMID:32707268). The integration of segregation information with variant characterization strengthens the causative link between PIGC mutations and intellectual disability. This robust genetic narrative is a cornerstone for clinical diagnostic decision-making.

Integration of the genetic and experimental evidence provides a coherent narrative regarding the pathogenic role of PIGC variants. The identified mutations, including c.635T>C (p.Leu212Pro), define a mutational spectrum that encompasses both missense and truncating changes, contributing to defective GPI-anchor biosynthesis. Functional assessments consistently demonstrate reduced expression of key surface proteins, thereby validating the impact of these genetic alterations. While the number of affected probands is relatively limited, the replication of findings across independent studies attests to the robustness of the association. The convergence of genetic, segregation, and functional data not only supports the diagnostic utility of testing for PIGC variants but also paves the way for future research into targeted therapies. Key take‑home: PIGC mutations are a critical contributor to intellectual disability and should be considered in comprehensive neurogenetic diagnostic panels.

References

• Journal of medical genetics • 2017 • Mutations in the phosphatidylinositol glycan C (PIGC) gene are associated with epilepsy and intellectual disability PMID:27694521
• European journal of medical genetics • 2020 • Multisystem disorders, severe developmental delay and seizures in two affected siblings, expanding the phenotype of PIGC deficiency PMID:32707268

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