title: A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2.
abstract: Hypomorphic germline mutations in the PIGA (phosphatidylinositol glycan class A) gene recently were recognized as the cause of a clinically heterogeneous spectrum of X-linked disorders including (i) early onset epileptic encephalopathy with severe muscular hypotonia, dysmorphism, multiple congenital anomalies, and early death ("MCAHS2"), (ii) neurodegenerative encephalopathy with systemic iron overload (ferro-cerebro-cutaneous syndrome, "FCCS"), and (iii) intellectual disability and seizures without dysmorphism. Previous studies showed that the recurrent PIGA germline mutation c.1234C>T (p.Arg412*) leads to a clinical phenotype at the most severe end of the spectrum associated with early infantile lethality. We identified three additional individuals from two unrelated families with the same PIGA mutation. Major clinical findings include early onset intractable epileptic encephalopathy with a burst-suppression pattern on EEG, generalized muscular hypotonia, structural brain abnormalities, macrocephaly and increased birth weight, joint contractures, coarse facial features, widely spaced eyes, a short nose with anteverted nares, gingival overgrowth, a wide mouth, short limbs with short distal phalanges, and a small penis. Based on the phenotypic overlap with Simpson-Golabi-Behmel syndrome type 2 (SGBS2), we hypothesized that both disorders might have the same underlying cause. We were able to confirm the same c.1234C>T (p.Arg412*) mutation in the DNA sample from an affected fetus of the original family affected with SGBS2. We conclude that the recurrent PIGA germline mutation c.1234C>T leads to a recognizable clinical phenotype with a poor prognosis and is the cause of SGBS2.
authors.affiliation: Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Fauth
authors.affiliation: Institute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
authors.forename: Katharina
authors.initials: K
authors.lastname: Steindl
authors.affiliation: Department of Genetics, Tours University Hospital, Tours, France.
authors.forename: Annick
authors.initials: A
authors.lastname: Toutain
authors.affiliation: Department of Laboratory Medicine and Genetics, Trillium Health Partners, Credit Valley Hospital, Mississauga, Ontario, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Farrell
authors.affiliation: Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Martina
authors.initials: M
authors.lastname: Witsch-Baumgartner
authors.affiliation: Clinic for Pediatrics I, Inherited Metabolic Disorders, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Daniela
authors.initials: D
authors.lastname: Karall
authors.affiliation: Institute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
authors.forename: Pascal
authors.initials: P
authors.lastname: Joset
authors.affiliation: Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Böhm
authors.affiliation: Institute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.affiliation: Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Maier
authors.affiliation: Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Johannes
authors.initials: J
authors.lastname: Zschocke
authors.affiliation: Division of Clinical and Metabolic Genetics, The Hospital for Sick Children, Toronto, Ontario, Canada.|Genetics and Genome Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada.|Institute of Medical Science and Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Rosanna
authors.initials: R
authors.lastname: Weksberg
authors.affiliation: Department of Pediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Ontario, Canada.|The Centre for Applied Genomics, Genetics and Genome Biology, The Hospital for Sick Children, Toronto, Ontario, Canada.
authors.forename: Christian R
authors.initials: CR
authors.lastname: Marshall
authors.affiliation: Institute of Medical Genetics, University of Zürich, Schlieren-Zürich, Switzerland.
authors.forename: Anita
authors.initials: A
authors.lastname: Rauch
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D002648:Child; D005260:Female; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype
chemical_list: D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein
keywords: GPI anchor; PIGA; Simpson Golabi Behmel syndrome type 2; germline mutation