AUTHOR=Ben Ayed Ikhlas , Jallouli Olfa , Murakami Yoshiko , Souissi Amal , Mallouli Salma , Bouzid Amal , Kamoun Fatma , Elloumi Ines , Frikha Fakher , Tlili Abdelaziz , Weckhuysen Sarah , Kinoshita Taroh , Triki Chahnez Charfi , Masmoudi Saber 

TITLE=Case report: Functional analysis of the p.Arg507Trp variant of the PIGT gene supporting the moderate epilepsy phenotype of mutations in the C-terminal region

JOURNAL=Frontiers in Neurology

VOLUME=Volume 14 - 2023

YEAR=2023

URL=https://www.frontiersin.org/journals/neurology/articles/10.3389/fneur.2023.1092887

DOI=10.3389/fneur.2023.1092887

ISSN=1664-2295

ABSTRACT=Pathogenic germline variants in PIGT gene are associated with “multiple congenital anomalies–hypotonia-seizures syndrome 3 (MCAHS3)” phenotype. So far, fifty patients have been reported, most of them suffer from intractable epilepsy. Recently, comprehensive analysis of a cohort of 26 patients with PIGT variants broadened the phenotypical spectrum and showed that both Asn527Ser and Val528Met are associated with a milder epilepsy phenotype and less severe outcome. Since all reported patients are of Caucasian/Polish origin and most of them harbouring the same variant Val528Met, a definitive conclusion regarding the genotype-phenotype correlation remains limited. 
We report a new case with a homozygous variant p.Arg507Trp in PIGT gene detected on clinical-exome sequencing. The North African patient displays a predominantly neurological phenotype with global developmental delay, hypotonia, brain abnormalities, and well controlled epileptic seizures. Homozygous and heterozygous variants in codon 507 have been reported to cause PIGT deficiency without biochemical confirmation. In this study, FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the p.Arg507Trp led to mildly reduced activity. Our result confirmed the pathogenicity of this variant and strengthens recently reported genotype-phenotype correlation of PIGT variant.