Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
This summary details the association between biallelic pathogenic variants in PIGQ and infantile epileptic‐dyskinetic encephalopathy. Multiple independent studies have identified affected children who presented with epileptic seizures, global developmental delay, axial hypotonia, and gastrointestinal malformations. The evidence was gathered through clinical exome sequencing, extensive phenotyping, and evaluation of congenital anomalies, thus underscoring the clinical relevance of PIGQ in this early‐onset disorder (PMID:32588908).
Genetic evidence supports an autosomal recessive mode of inheritance. In one study, seven children from six unrelated families were identified with biallelic variants in PIGQ, reinforcing the disease mechanism through multi‑family segregation and replication of similar loss‐of‐function events. An exemplar variant, c.1333C>T (p.Gln445Ter), demonstrates the typical pathogenic spectrum seen in affected individuals (PMID:32588908). Another study applying whole‐genome sequencing further implicated PIGQ through recessive mutation detection in a case of early‑onset epilepsy (PMID:24463883).
The cumulative case series and familial studies provide strong genetic evidence. Multiple variants—including deleterious splice site changes, frameshift deletions, and nonsense mutations—have been reported across the spectrum of affected subjects. Genetic analysis indicates that these variants are rare and segregate with the clinical phenotype, thereby increasing the confidence in the gene‑disease relationship (PMID:32588908; PMID:24463883).
Functional studies further corroborate the clinical findings. Patient‐derived fibroblasts demonstrated reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins, a defect that was fully rescued by transfection with wild‑type PIGQ cDNA. These findings support a loss‑of‑function mechanism consistent with the phenotypic manifestations of the disorder, thereby reinforcing the pathogenicity of the reported genetic defects (PMID:32588908).
Although additional studies have examined variants in other neurodevelopmental and neuropsychiatric disorders, the evidence linking PIGQ to infantile epileptic‑dyskinetic encephalopathy is specific and robust. These investigations reveal a nuanced spectrum of disease manifestations, yet the core phenotype of early‑onset epilepsy with dyskinetic features consistently emerges across multiple cohorts.
In summary, the integration of case reports, segregation studies, and functional assessments supports a strong gene‑disease relationship. The clinical utility of this association is underscored by its potential to inform diagnostic decision‑making and guide therapeutic strategies in affected patients.
Gene–Disease AssociationStrongSeven probands from one study (PMID:32588908) and additional recessive cases with congruent clinical features in a separate cohort (PMID:24463883) and supporting functional data establish a strong association. Genetic EvidenceStrongMultiple families exhibit autosomal recessive inheritance with a broad spectrum of loss-of-function variants, including c.1333C>T (p.Gln445Ter), which have been consistently identified in affected individuals. Functional EvidenceModerateFlow cytometry and rescue experiments in patient fibroblasts demonstrate defective GPI-anchoring that is restored upon wild-type PIGQ cDNA transfection, supporting a loss-of-function mechanism. |