Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report

Abstract

Background Mutations in PIGN, resulting in a glycosylphosphatidylinositol (GPI) anchor deficiency, typically leads to multiple congenital anomalies-hypotonia-seizures syndrome. However, the link between PIGN and epilepsy or paroxysmal non-kinesigenic dyskinesia (PNKD) is not well-described. This study reported a patient with PIGN mutation leading to developmental and epileptic encephalopathy and PNKD, to expand upon the genotype–phenotype correlation of PIGN. Case presentation During the first 10 days of life, a girl exhibited paroxysmal staring episodes with durations that ranged from several minutes to hours. These episodes occurred 2–5 times daily and always occurred during wakefulness. Ictal electroencephalography revealed no abnormalities, and PNKD was diagnosed. The patient also exhibited severely delayed psychomotor development and generalized seizures at the age of 4 months. Results of brain magnetic resonance imaging and metabolic screenings were normal, but trio-based whole-exome sequencing identified two novel compound heterozygous PIGN mutations (NM_176787; c.163C > T [p.R55 > X] and c.283C > T [p.R95W]). Flow cytometry analysis of the patient’s granulocytes revealed dramatically reduced expression of GPI-anchored proteins. This indicated that the mutations compromised GPI functions. The patient got seizure-free for 1 year, and her dyskinesia episodes reduced significantly (1–2 times/month) after treatment with levetiracetam (600 mg/day) and clonazepam (1.5 mg/day). No progress was observed with respect to psychomotor development; however, no craniofacial dysmorphic features, cleft lip/palate, brachytelephalangy with nail hypoplasia, and internal malformations have been observed until now (6 years of age). Conclusion This is the first study to document developmental and epileptic encephalopathy with PNKD in a human with PIGN mutations. This report expanded our understanding of the genotype–phenotype correlation of PIGN, and PIGN may be considered a potentially relevant gene when investigating cases of epilepsy or PNKD.

The genetic landscape of autism spectrum disorder in the Middle Eastern population

“…This mutation was rare in the gnomAD database (MAF = 0.0007, homozygous count = 1) and predicted to be pathogenic. The PIGN protein is involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis, and homozygous pathogenic variants in PIGN have been reported in patients with multiple congenital anomalies, including delayed psychomotor development, hypotonia, and seizures ( Maydan et al, 2011 ; Tian et al, 2022 ). Our data reveal the complex genetic architecture of ASD and identify two homozygous variants in genes involved in neuronal development.…”

PIGN c.776T>C (p.Phe259Ser) variant present in trans with a pathogenic variant for PIGN-congenital disorder of glycosylation: Bella-Noah syndrome

“…Loong et al [ 16 ] described 21 patients that together with other 40 patients presented in the literature account for 61 patients with biallelic PIGN variants [ 16 ]. The symptoms of biallelic PIGN variants usually includes psychomotor development delay, hypotonia, seizures and dysmorphic features [ 10 ]. The most commonly reported PIGN disease related variant is the c.932T > G. All reported individuals with this missense variant were compound heterozygous with a different second variant [ 17 ].…”

“…The PIGN (phosphatidylinositol glycan anchor biosynthesis class N) gene (OMIM* 606097) is located on chromosome 18q21.33 and is composed of 31 exons (29 coding) spanning 142.8 kb, and encoding a glycosylphosphatidylinositol ethanolamine phosphate transferase 1, a protein with 931 amino acids involved in the glycosylphosphatidylinositol (GPI)-anchor biosynthesis pathway, a deeply conserved process that enables proteins to bind to the cell surface membrane [ [6] , [7] , [8] , [9] , [10] ]. PIGN is responsible for the addition of phosphoethanolamine to the first mannose in the GPI [ 8 ].…”

“…Multiple congenital anomalies-hypotonia-seizures syndrome1 (MCAHS1) (OMIM# 614080 ) and Fryns syndrome (OMIM# 229850 ) are usually caused by mutations in the PIGN gene, resulting in a GPI anchor deficiency [ 10 , 11 ]. Nonetheless, some individuals who have PIGN mutations do not meet all the criteria for syndrome diagnosis [ 10 ].…”

Identification of candidate genomic regions for thermogelled egg yolk traits based on a genome-wide association study

“…RELCH is a Rab11-GTP-binding protein involved in the transport and distribution of cholesterol through interaction with OSBP ( Sobajima et al, 2018 ). PIGN encodes an enzyme involved in the biosynthesis of glycosylphosphatidylinositol, which anchors various proteins to the cell surface ( Tian et al, 2022 ). RNF152 regulates body fat production ( Silva et al, 2019 ).…”