CHIME Syndrome in a Child With Homozygous PIGL p.Leu167Pro Variant

Area of Science:

• Genetics
• Dermatology
• Pediatrics

Background:

• CHIME syndrome is a rare autosomal recessive disorder characterized by ichthyosiform dermatosis, intellectual disability, ocular colobomas, ear anomalies, and heart defects.
• It is caused by biallelic pathogenic variants in the PIGL gene.
• Previously, all reported individuals with CHIME syndrome carried the PIGL c.500T>C p.Leu167Pro variant on one allele, alongside another PIGL variant on the second allele.

Observation:

• A 6-year-old girl with CHIME syndrome presented with homozygous PIGL p.Leu167Pro variants.
• This presentation challenges the hypothesis that the p.Leu167Pro variant confers a mild phenotype, as the patient exhibited a significant phenotype.

Findings:

• The identification of a patient with homozygous PIGL p.Leu167Pro variants refutes the prior assumption that this variant only has a mild phenotypic effect when present with another PIGL variant.
• This finding suggests that homozygous pathogenic variants, particularly founder variants in rare conditions like CHIME syndrome, may be more common than previously thought, especially in offspring of consanguineous parents.

Implications:

• The existence of homozygous p.Leu167Pro variants indicates that the PIGL gene's role in CHIME syndrome is complex and not solely dependent on the combination of variants.
• Future research should consider the possibility of homozygous pathogenic variants in CHIME syndrome cases, potentially increasing the diagnostic yield.
• This case highlights the importance of considering homozygous mutations in rare genetic disorders, especially in specific populations.