PIGM and Congenital Disorder of Glycosylation

PIGM encodes an enzyme essential for glycosylphosphatidylinositol (GPI) anchor biosynthesis. An association has been established between mutations in this gene and congenital disorder of glycosylation (MONDO_0015286). Affected individuals present with a distinct phenotype characterized by portal vein thrombosis, macrocephaly, and atypical absence seizures. Multi‐patient studies have identified a promoter mutation in PIGM that is observed in patients from independent families. The mutation’s co‐segregation with the disease, along with its rarity in the general population, supports its pathogenic role. This finding has significant implications for clinical diagnosis and targeted genetic testing.

Clinical validity for the association is rated as Strong. A total of seven probands have been reported across two unrelated families with positive segregation analyses, which confirms the autosomal recessive inheritance pattern. The collective data from these multi‐patient studies provide robust genetic support, thereby meeting key ClinGen criteria. Although a coding change was not identified, the promoter mutation exhibits a clear detrimental effect on gene regulation. Further, the genetic evidence is bolstered by the recurrence of the mutation in distinct patient cohorts. This overall evidence base underlines the clinical relevance of PIGM testing in suspected cases.

Genetic evidence is derived from detailed family studies and case series that demonstrate the segregation of the PIGM promoter mutation with the disease phenotype. While a specific coding variant was not provided in the congenital disorder report, the identified promoter mutation is strongly implicated in disrupting normal gene expression. In two unrelated families, segregation analysis confirmed that the mutation co‐occurs with disease symptoms. The mutation appears to be rare and, importantly, has been consistently observed across independent studies. These findings provide moderate genetic evidence by reinforcing the role of altered transcriptional regulation in the disease mechanism. Such genetic data are crucial for supporting further clinical diagnostic evaluations.

Functional studies have contributed key insights into the pathogenic mechanism. Experimental evidence reveals that the promoter mutation disrupts SP1 binding, leading to decreased expression of PIGM and subsequently reduced GPI-anchor synthesis. In vitro assays demonstrated a significant impact on the cell-surface presentation of GPI-anchored proteins. These functional perturbations closely recapitulate the clinical phenotype observed in affected patients. Cellular models confirm that the decreased expression directly impairs GPI-anchor remodeling. Overall, these functional data provide moderate support for the causal role of the variant in disease.

Integrating both genetic and experimental evidence, the association between PIGM (HGNC:18858) and congenital disorder of glycosylation (MONDO_0015286) is well substantiated. The robust segregation data across multiple families, combined with functional assays demonstrating disrupted SP1-mediated transcription, underscore the pathogenicity of the promoter mutation. Although a coding variant was not identified in these cases, the promoter mutation’s effect on gene expression offers a clear mechanistic link to the clinical phenotype. This integrated evidence supports its clinical utility for diagnostic decision-making and may inform potential therapeutic strategies. The convergence of genetic and functional findings allows clinicians to confidently include PIGM in diagnostic panels for congenital glycosylation disorders. Key take‑home: Genetic testing for PIGM mutations can significantly aid in the early diagnosis and management of congenital disorder of glycosylation.

References

• Molecular genetics and metabolism • 2019 • Cerebral and portal vein thrombosis, macrocephaly and atypical absence seizures in Glycosylphosphatidyl inositol deficiency due to a PIGM promoter mutation PMID:31445883
• Birth defects research. Part C, Embryo today : reviews • 2009 • Inherited GPI deficiency: a disorder of histone hypoacetylation PMID:19960552

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