PIGG – Intellectual Disability

This summary integrates evidence from multiple independent studies demonstrating a strong association between pathogenic variants in PIGG and intellectual disability. A recent case report detailed an Iranian family in which a novel PIGG mutation was identified, with comprehensive in silico analyses supporting its disruptive effect on glycosylphosphatidylinositol (GPI) anchor biosynthesis (PMID:31414351).

In the Iranian family study, exome sequencing identified the variant c.1972C>G (p.Pro658Ala) as a likely pathogenic change, and the autosomal recessive inheritance pattern was confirmed. This variant, along with in silico structural modeling, strongly implicated impaired function of the encoded ethanolamine phosphate transferase, further linking PIGG dysfunction with the intellectual disability phenotype (PMID:31414351).

Supporting evidence comes from multi-patient studies that have examined copy number variations in subtelomeric regions, where deletions involving PIGG have been observed in patients with developmental and intellectual disabilities (PMID:27665090). Furthermore, studies including 22 individuals from 19 unrelated families have reported multiple variant classes, including missense, nonsense, and frameshift mutations in PIGG (PMID:34113002).

Functional assessments in patient-derived fibroblasts have provided moderate experimental support by documenting reduced cell surface levels of GPI-anchored proteins. These functional studies substantiate a loss-of-function mechanism, which is consistent with the impaired biosynthesis of GPI anchors observed in affected individuals (PMID:28581210).

Segregation analyses across the 19 families further bolster the evidence by demonstrating autosomal recessive inheritance and the occurrence of pathogenic variants in multiple affected relatives, providing robust genetic evidence for the PIGG–intellectual disability association. The convergence of genetic data, family segregation, and functional assays underscores a strong gene–disease relationship.

In conclusion, the integration of case studies, multi-patient genetic evaluations, and functional experiments provides compelling diagnostic evidence for PIGG as a contributor to intellectual disability. This synthesis supports clinical decision-making, commercial diagnostic development, and future research publication, emphasizing that identifying PIGG variants can directly inform patient care and genetic counseling.

References

• Journal of molecular neuroscience : MN • 2019 • Identification and In Silico Characterization of a Novel Point Mutation in PIGG in an Iranian Family PMID:31414351
• Cytogenetic and genome research • 2016 • Subtelomeric Copy Number Variations in Developmental Disability PMID:27665090
• 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)