title: Novel PIGT Variant in Two Brothers: Expansion of the Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 Phenotype.
abstract: BiallelicPIGTvariants were previously reported in seven patients from three families with Multiple Congenital Anomalies-Hypotonia Seizures Syndrome 3 (MCAHS3), characterized by epileptic encephalopathy, hypotonia, global developmental delay/intellectual disability, cerebral and cerebellar atrophy, craniofacial dysmorphisms, and skeletal, ophthalmological, cardiac, and genitourinary abnormalities. We report a novel homozygousPIGTmissense variant c.1079G>T (p.Gly360Val) in two brothers with several of the typical features of MCAHS3, but in addition, pyramidal tract neurological signs. Notably, they are the first patients with MCAHS3 without skeletal, cardiac, or genitourinary anomalies.PIGTencodes a crucial subunit of the glycosylphosphatidylinositol (GPI) transamidase complex, which catalyzes the attachment of proteins to GPI-anchors, attaching the proteins to the cell membrane. In vitro studies in cells from the two brothers showed reduced levels of GPI-anchors and GPI-anchored proteins on the cell surface, supporting the pathogenicity of the novelPIGTvariant.
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway. nadia.skauli@medisin.uio.no.|Faculty of Medicine, University of Oslo, 0450 Oslo, Norway. nadia.skauli@medisin.uio.no.
authors.forename: Nadia
authors.initials: N
authors.lastname: Skauli
authors.affiliation: Department of Clinical Neurosciences for Children, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, 0450 Oslo, Norway. s.c.wallace@medisin.uio.no.
authors.forename: Sean
authors.initials: S
authors.lastname: Wallace
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine, Karolinska University Hospital Huddinge, 14157 Stockholm, Sweden. samuel.chiang-cern-cher@ki.se.
authors.forename: Samuel C C
authors.initials: SC
authors.lastname: Chiang
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway. tuva.baroy@medisin.uio.no.|Faculty of Medicine, University of Oslo, 0450 Oslo, Norway. tuva.baroy@medisin.uio.no.
authors.forename: Tuva
authors.initials: T
authors.lastname: Barøy
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway. asbjorn.holmgren@medisin.uio.no.uio.no.|Faculty of Medicine, University of Oslo, 0450 Oslo, Norway. asbjorn.holmgren@medisin.uio.no.uio.no.
authors.forename: Asbjørn
authors.initials: A
authors.lastname: Holmgren
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway. astraype@ous-hf.no.
authors.forename: Asbjørg
authors.initials: A
authors.lastname: Stray-Pedersen
authors.affiliation: Center for Hematology and Regenerative Medicine (HERM), Department of Medicine, Karolinska University Hospital Huddinge, 14157 Stockholm, Sweden. yenan.bryceson@ki.se.
authors.forename: Yenan T
authors.initials: YT
authors.lastname: Bryceson
authors.affiliation: Faculty of Medicine, University of Oslo, 0450 Oslo, Norway. petter.stromme@medisin.uio.no.|Department of Clinical Neurosciences for Children, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, 0450 Oslo, Norway. petter.stromme@medisin.uio.no.
authors.forename: Petter
authors.initials: P
authors.lastname: Strømme
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway. eirik.frengen@medisin.uio.no.|Faculty of Medicine, University of Oslo, 0450 Oslo, Norway. eirik.frengen@medisin.uio.no.
authors.forename: Eirik
authors.initials: E
authors.lastname: Frengen
authors.affiliation: Department of Medical Genetics, Oslo University Hospital, 0450 Oslo, Norway. doriana.misceo@medisin.uio.no.|Faculty of Medicine, University of Oslo, 0450 Oslo, Norway. doriana.misceo@medisin.uio.no.
authors.forename: Doriana
authors.initials: D
authors.lastname: Misceo
keywords: GPI-anchors; MCAHS3; PIGT; cerebellar atrophy; craniofacial dysmorphism; developmental delay; epilepsy