PIGQ glycosylphosphatidylinositol‐anchored protein deficiency: Characterizing the phenotype

Abstract

PIGQ (OMIM *605754) encodes phosphatidylinositol glycan biosynthesis class Q (PIGQ) and is required for proper functioning of an N‐acetylglucosamine transferase complex in a similar manner to the more established PIGA, PIGC, and PIGH. There are two previous patients reported with homozygous and apparently deleterious PIGQ mutations. Here, we provide the first detailed clinical report of a patient with heterozygous deleterious mutations associated with glycosylphosphatidylinositol‐anchored protein (GPI‐AP) biosynthesis deficiency. Our patient died at 10 months of age. The rare skeletal findings in this disorder expand the differential diagnosis of long bone radiolucent lesions and sphenoid wing dysplasia. This clinical report describes a new and rare disorder—PIGQ GPI‐AP biosynthesis deficiency syndrome.

Early infantile epileptic encephalopathy due to biallelic pathogenic variants in PIGQ: Report of seven new subjects and review of the literature

“…Most affected individuals with biallelic PIGQ variants have delayed myelination, but generally lack gross structural lesions on MRI. Of note, while the affected individual reported by Starr et al 15 had significant left‐sided ventriculomegaly, we did not observe this in our cohort. A limiting factor could be that our subjects generally underwent MRI before the age of 10 months and that a long‐term follow‐up of MRI findings was not available.…”

“…Individuals with pathogenic variants affecting other genes in the pathway have shown development of both cerebral and cerebellar loss of tissue over time. 17,18 While we also did not observe long bone radiolucent lesions as previously described, 15 skeletal anomalies and delayed dentition were common. Of note, St4 and St5 had midgut volvulus requiring surgery, and St5 had a duodenal web requiring resection.…”

“…While we also did not observe long bone radiolucent lesions as previously described, 15 skeletal anomalies and delayed dentition were common. Of note, St4 and St5 had midgut volvulus requiring surgery, and St5 had a duodenal web requiring resection.…”

“…We identified seven previously unreported PIGQ (NM_148920.2) variants predicted to be damaging and one previously identified variant (p.Y400del). 15 Table S2). Seizure outcome ranged from partially controlled with occasional breakthroughs with illness (St1 and St2), to recurrent status epilepticus (St4, St6), daily focal seizures (St6) or daily clustered myoclonic jerks (St5).…”

The Glycosylphosphatidylinositol biosynthesis pathway in human diseases

“…Watanabe et al demonstrated that PIG-Q is not an essential component of GPI-GnT because PIGQ-defective cells have some surface GPI-AP expression [62]. However, a recessive mutation in PIGQ gene have been reported in an Ohtahara Syndrome patient and a patient with profound developmental delay, dysmorphic features, hypotonia, vision problems, gastrostomy tube dependency [63,64]. The transcriptional level, the expression of mutant protein, and the GPI-APs (CD59) detected by qPCR, western blotting and flow cytometry, respectively, were greatly decreased.…”