title: Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy.
abstract: Mutations in PIGN, resulting in multiple congenital anomalies-hypotonia-seizures syndrome, a glycosylphosphatidylinositol anchor deficiency, have been published in four families to date. We report four patients from three unrelated families with epilepsy and hypotonia in whom whole exome sequencing yielded compound heterozygous variants in PIGN. As with previous reports Patients 1 and 2 (full siblings) have severe global developmental delay, gastroesophageal reflux disease, and minor dysmorphic features, including high palate, bitemporal narrowing, depressed nasal bridge, and micrognathia; Patient 3 had early global developmental delay with later progressive spastic quadriparesis, intellectual disability, and intractable generalized epilepsy; Patient 4 had bilateral narrowing as well but differed by the presence of hypertelorism, markedly narrow palpebral fissures, and long philtrum, had small distal phalanges of fingers 2, 3, and 4, absent distal phalanx of finger 5 and similar toe anomalies, underdeveloped nails, unusual brain anomalies, and a more severe early clinical course. These patients expand the known clinical spectrum of the disease. The severity of the presentations in conjunction with the patients' mutations suggest a genotype-phenotype correlation in which congenital anomalies are only seen in patients with biallelic loss-of-function. In addition, PIGN mutations appear to be panethnic and may be an underappreciated cause of epilepsy.
authors.affiliation: NHGRI, Office of the Clinical Director, NIH, Bethesda, Maryland.
authors.forename: Leah
authors.initials: L
authors.lastname: Fleming
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Monica
authors.initials: M
authors.lastname: Lemmon
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.|Greenberg Center for Skeletal Dysplasia, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Natalie
authors.initials: N
authors.lastname: Beck
authors.affiliation: Department of Neurology, University of Minnesota, Minneapolis, Minnesota.
authors.forename: Maria
authors.initials: M
authors.lastname: Johnson
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Weiyi
authors.initials: W
authors.lastname: Mu
authors.affiliation: NHGRI, Office of the Clinical Director, NIH, Bethesda, Maryland.
authors.forename: David
authors.initials: D
authors.lastname: Murdock
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Joann
authors.initials: J
authors.lastname: Bodurtha
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.|Greenberg Center for Skeletal Dysplasia, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Julie
authors.initials: J
authors.lastname: Hoover-Fong
authors.affiliation: The Hospital for Sick Children, Clinical and Metabolic Genetics, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Ronald
authors.initials: R
authors.lastname: Cohn
authors.affiliation: Section of Pediatric Neuroradiology, Division of Pediatric Radiology, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Thangamadhan
authors.initials: T
authors.lastname: Bosemani
authors.affiliation: Department of Neurology, Johns Hopkins University, Baltimore, Maryland.|Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, Maryland.
authors.forename: Kristin
authors.initials: K
authors.lastname: Barañano
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ada
authors.initials: A
authors.lastname: Hamosh
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D000293:Adolescent; D000328:Adult; D002648:Child; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000473:pathology; D004827:Epilepsy / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D005260:Female; D056726:Genetic Association Studies; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D009123:Muscle Hypotonia / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D010770:Phosphotransferases / Q000235:genetics*; D011379:Prognosis; D012640:Seizures / Q000151:congenital / Q000235:genetics* / Q000473:pathology; D013577:Syndrome; D055815:Young Adult
chemical_list: C561296:PIGN protein, human; D010770:Phosphotransferases
keywords: GPI ethanolamine phosphate transferase 1; PIGN; congenital disorders of glycosylation; epilepsy; genotype-phenotype association; glycosylphosphatidylinositol anchors; human; hypotonia; infantile; intractable; spasms