Lessons learned from 40 novel PIGA patients and a review of the literature.
Adult
Amino Acid Sequence
Child
Cohort Studies
Electroencephalography
/ methods
Facies
Genetic Variation
/ genetics
Hernia, Diaphragmatic
/ diagnostic imaging
Humans
Infant, Newborn
Limb Deformities, Congenital
/ diagnostic imaging
Magnetic Resonance Imaging
/ methods
Male
Membrane Proteins
/ genetics
PIGA
Fryns syndrome phenotype
bioinformatical comparison
genotype-phenotype correlation
mild developmental delay
Journal
Epilepsia
ISSN: 1528-1167
Titre abrégé: Epilepsia
Pays: United States
ID NLM: 2983306R
Informations de publication
Date de publication:
06 2020
06 2020
Historique:
received:
08
03
2020
revised:
26
04
2020
accepted:
27
04
2020
pubmed:
27
5
2020
medline:
1
12
2020
entrez:
27
5
2020
Statut:
ppublish
Résumé
To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome-like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.
Substances chimiques
Membrane Proteins
0
phosphatidylinositol glycan-class A protein
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
1142-1155Subventions
Organisme : European Academy of Dermatology and Venereology
ID : PPRC-2018-50
Pays : International
Organisme : Ghent University
ID : BOF-Start 01N04516
Pays : International
Organisme : European Union Seventh Framework Program
ID : FP7/2007-2013
Pays : International
Organisme : University of Kiel
Pays : International
Organisme : German Research Foundation
ID : HE 5415/5-1
Pays : International
Organisme : German Research Foundation
ID : HE 5415/6-1
Pays : International
Organisme : German Research Foundation
ID : FOR2715 HE5415/7-1
Pays : International
Organisme : Netherlands Organization for Scientific Research
ID : 9161702
Pays : International
Organisme : Brain & Behavior Research Foundation
Pays : International
Organisme : Danish National Research Foundation
ID : DNRF107
Pays : International
Informations de copyright
© 2020 International League Against Epilepsy.
Références
Fujita M, Kinoshita T. GPI-anchor remodeling: potential functions of GPI-anchors in intracellular trafficking and membrane dynamics. Biochim Biophys Acta. 2012;1821(8):1050-8.
Kinoshita T, Fujita M. Biosynthesis of GPI-anchored proteins: special emphasis on GPI lipid remodeling. J Lipid Res. 2016;57:6-24.
Bellai-Dussault K, Nguyen TTM, Baratang NV, Jimenez-Cruz DA, Campeau PM. Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders. Clin Genet. 2019;95:112-21.
Watanabe R, Kinoshita T, Masaki R, Yamamoto A, Takeda J, Inoue N. PIG-A and PIG-H, which participate in glycosylphosphatidylinositol anchor biosynthesis, form a protein complex in the endoplasmic reticulum. J Biol Chem. 1996;271:26868-75.
Watanabe R, Inoue N, Westfall B, et al. The first step of glycosylphosphatidylinositol biosynthesis is mediated by a complex of PIG-A, PIG-H, PIG-C and GPI1. EMBO J. 1998;17:877-85.
Miyata T, Takeda J, Iida Y, et al. The cloning of PIG-A, a component in the early step of GPI-anchor biosynthesis. Science. 1993;259:1318-20.
Eisenhaber B, Maurer-Stroh S, Novatchkova M, Schneider G, Eisenhaber F. Enzymes and auxiliary factors for GPI lipid anchor biosynthesis and post-translational transfer to proteins. Bioessays. 2003;25:367-85.
Johnston J, Gropman A, Sapp J, et al. The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet. 2012;90:295-300.
Kato M, Saitsu H, Murakami Y, et al. PIGA mutations cause early-onset epileptic encephalopathies and distinctive features. Neurology. 2014;82:1587-96.
Belet S, Fieremans N, Yuan X, et al. Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality. Hum Mutat. 2014;35:350-5.
Kim YO, Yang JH, Park C, et al. A novel PIGA mutation in a family with X-linked, early-onset epileptic encephalopathy. Brain Dev. 2016;38:750-4.
Joshi C, Kolbe DL, Mansilla MA, Mason S, Smith RJ, Campbell CA. Ketogenic diet-a novel treatment for early epileptic encephalopathy due to PIGA deficiency. Brain Dev. 2016;38:848-51.
Fauth C, Steindl K, Toutain A, et al. A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2. Am J Med Genet A. 2016;170A:392-402.
van der Crabben SN, Harakalova M, Brilstra EH, et al. Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities. Am J Med Genet A. 2014;164A:29-35.
Swoboda KJ, Margraf RL, Carey JC, et al. A novel germline PIGA mutation in ferro-cerebro-cutaneous syndrome: a neurodegenerative X-linked epileptic encephalopathy with systemic iron-overload. Am J Med Genet A. 2014;164A:17-28.
Tarailo-Graovac M, Sinclair G, Stockler-Ipsiroglu S, et al. The genotypic and phenotypic spectrum of PIGA deficiency. Orphanet J Rare Dis. 2015;10:23.
Soden SE, Saunders CJ, Willig LK, et al. Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med. 2014;6:265ra168.
Xie LL, Song XJ, Li TY, Jiang L. A novel germline PIGA mutation causes early-onset epileptic encephalopathies in Chinese monozygotic twins. Brain Dev. 2018;40:596-600.
Low KJ, James M, Sharples PM, et al. A novel PIGA variant associated with severe X-linked epilepsy and profound developmental delay. Seizure. 2018;56:1-3.
Lin WD, Chou IC, Tsai FJ, Hong SY. A novel PIGA mutation in a Taiwanese family with early-onset epileptic encephalopathy. Seizure. 2018;58:52-4.
Olson HE, Kelly MK, LaCoursiere CM, et al. Genetics and genotype-phenotype correlations in early onset epileptic encephalopathy with burst suppression. Ann Neurol. 2017;81:419-29.
Fokstuen S, Makrythanasis P, Hammar E, et al. Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders. Hum Genomics. 2016;10:24.
Yang J, Wang Q, Zhuo Q, et al. A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia-seizures syndrome 2 (MCAHS2) family pedigree via whole-exome sequencing. Mol Genet Genomic Med. 2018;6:739-48.
Trump N, McTague A, Brittain H, et al. Improving diagnosis and broadening the phenotypes in early-onset seizure and severe developmental delay disorders through gene panel analysis. J Med Genet. 2016;53:310-7.
Zhu X, Petrovski S, Xie P, et al. Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med. 2015;17:774-81.
Traynelis J, Silk M, Wang Q, et al. Optimizing genomic medicine in epilepsy through a gene-customized approach to missense variant interpretation. Genome Res. 2017;27:1715-29.
Grantham R. Amino acid difference formula to help explain protein evolution. Science. 1974;185:862-4.
Dewey FE, Murray MF, Overton JD, et al. Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study. Science. 2016;354. pii: aaf6814.
Omasits U, Ahrens CH, Müller S, Wollscheid B. Protter: interactive protein feature visualization and integration with experimental proteomic data. Bioinformatics. 2014;30:884-6.
Burgess R, Wang S, McTague A, et al. The genetic landscape of epilepsy of infancy with migrating focal seizures. Ann Neurol. 2019;86:821-31.
Tranebjaerg L, Svejgaard A, Lykkesfeldt G. X-linked mental retardation associated with psoriasis: a new syndrome? Am J Med Genet. 1988;30:263-73.
Møller RS, Liebmann N, Larsen LHG, et al. Parental mosaicism in epilepsies due to alleged de novo variants. Epilepsia. 2019;60:e63-6.
Kuki I, Takahashi Y, Okazaki S, et al. Vitamin B6-responsive epilepsy due to inherited GPI deficiency. Neurology. 2013;81:1467-9.
Taketani T. Neurological symptoms of hypophosphatasia. Subcell Biochem. 2015;76:309-22.
Wilson MP, Plecko B, Mills PB, Clayton PT. Disorders affecting vitamin B6 metabolism. J Inherit Metab Dis. 2019;42:629-46.
Thompson MD, Killoran A, Percy ME, Nezarati M, Cole DE, Hwang PA. Hyperphosphatasia with neurologic deficit: a pyridoxine-responsive seizure disorder? Pediatr Neurol. 2006;34:303-7.
Tarutani M, Itami S, Okabe M, et al. Tissue-specific knockout of the mouse Pig-a gene reveals important roles for GPI-anchored proteins in skin development. Proc Natl Acad Sci U S A. 1997;94:7400-505.
Thompson MD, Cole DE. Recessive PIGN mutations in Fryns syndrome: evidence for genetic heterogeneity. Hum Mutat. 2016;37:621.
Alessandri JL, Gordon CT, Jacquemont ML, et al. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Reunion Island, in patients with Fryns syndrome. Eur J Hum Genet. 2018;26:340-9.
Terespolsky D, Farrell SA, Siegel-Bartelt J, Weksberg R. Infantilelethal variant of Simpson-Golabi-Behmel syndrome associated withhydrops fetalis. Am J Med Genet. 1995;59:329-333.