PIGL – CHIME Syndrome

This summary describes the robust association between variants in PIGL (HGNC:8966) and CHIME syndrome (MONDO_0010221), a rare autosomal recessive neuroectodermal disorder. CHIME syndrome is clinically characterized by colobomas, congenital heart defects, ichthyosiform dermatosis, and ear anomalies (PMID:39641205). The available data derive from multiple independent studies, each of which has identified recurrent variants in PIGL contributing to the disease phenotype.

Several case reports and multi‐patient studies have highlighted a recurrent missense mutation, c.500T>C (p.Leu167Pro), as a major contributor to the clinical presentation of CHIME syndrome (PMID:28371479; PMID:22444671). In these studies, affected individuals consistently demonstrated biallelic variants with the c.500T>C mutation being present in either compound heterozygous or homozygous states.

Segregation analyses in several families have provided strong additional evidence for this association. For instance, in one report the variant was inherited in a compound heterozygous manner with clear segregation of the mutation from unaffected parents, while a recent study described a homozygous occurrence in a 6-year-old patient, further supporting the autosomal recessive inheritance of the disorder (PMID:39641205). Such segregation data, along with supportive case numbers, underlie the strength of the gene-disease association.

Genetic evidence for the association is substantiated by the detection of multiple classes of pathogenic variants in PIGL. In addition to the recurrent c.500T>C (p.Leu167Pro) missense variant, other variant types including frameshift and deletion mutations have been reported in patients with CHIME syndrome, expanding the allelic spectrum. The identification of these variants across unrelated probands further reinforces the causative role of PIGL disruptions in this syndrome (PMID:28371479).

Functional studies have demonstrated that PIGL mutations disrupt glycosylphosphatidylinositol (GPI) anchor biosynthesis, which is critical for the cell surface expression of a variety of proteins. In vitro assays utilizing cell models have confirmed that mutant PIGL leads to reduced levels of GPI-anchored proteins, thereby linking the molecular defect to the pathophysiology of CHIME syndrome (PMID:27100116). This experimental evidence highlights the mechanistic impact of PIGL alterations and supports their pathogenicity.

Although one study described similar variants in patients with hyperphosphatasia with intellectual disability syndrome, careful phenotypic delineation has allowed clear distinction between the Mabry syndrome phenotype and CHIME syndrome. The clinical features of CHIME syndrome, particularly the characteristic colobomas and ear anomalies, are consistently observed in patients with PIGL mutations when compared to the broader phenotypic spectrum of GPI-anchor disorders.

In conclusion, the combined genetic and functional evidence provides a compelling narrative for the strong association between PIGL variants and CHIME syndrome. The recurrent identification of the c.500T>C (p.Leu167Pro) variant along with supportive segregation data and in vitro functional assays substantiates the use of genetic testing for diagnostic decision-making and further development of targeted therapies. This association not only informs clinical practice but is also of significant relevance for commercial diagnostics and future publication.

Key Take‑home sentence: The robust genetic and functional evidence for PIGL mutations in CHIME syndrome endorses its clinical utility as a diagnostic marker in this rare autosomal recessive disorder.

References

• American journal of medical genetics. Part A • 2025 • CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant PMID:39641205
• American journal of human genetics • 2012 • Mutations in the glycosylphosphatidylinositol gene PIGL cause CHIME syndrome PMID:22444671
• American journal of medical genetics. Part A • 2017 • Alu-mediated deletion of PIGL in a Patient with CHIME syndrome PMID:28371479
• Archives of toxicology • 2016 • The in vitro PIG-A gene mutation assay: glycosylphosphatidylinositol (GPI)-related genotype-to-phenotype relationship in TK6 cells PMID:27100116

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