Pagnamenta, AT;
Murakami, Y;
Taylor, JM;
Anzilotti, C;
Howard, MF;
Miller, V;
Johnson, DS;
Tadros, S;
Mansour, S;
Temple, IK;
et al.
Pagnamenta, AT; Murakami, Y; Taylor, JM; Anzilotti, C; Howard, MF; Miller, V; Johnson, DS; Tadros, S; Mansour, S; Temple, IK; Firth, R; Rosser, E; Harrison, RE; Kerr, B; Popitsch, N; DDD Study; Kinoshita, T; Taylor, JC; Kini, U
(2017)
Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.
Eur J Hum Genet, 25 (6).
pp. 669-679.
ISSN 1476-5438
https://doi.org/10.1038/ejhg.2017.32
SGUL Authors: Mansour, Sahar Mansour, Sahar
Abstract
Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing.
Item Type: |
Article
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Additional Information: |
This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/
© The Author(s) 2017 |
Keywords: |
Acyltransferases, Adult, Child, Developmental Disabilities, Exome, HEK293 Cells, Heterozygote, Homozygote, Humans, Membrane Proteins, N-Acetylglucosaminyltransferases, Pedigree, Phosphotransferases, Polymorphism, Single Nucleotide, Receptors, Cell Surface, Genetics & Heredity, 0604 Genetics |
SGUL Research Institute / Research Centre: |
Academic Structure > Molecular and Clinical Sciences Research Institute (MCS) |
Journal or Publication Title: |
Eur J Hum Genet |
ISSN: |
1476-5438 |
Language: |
eng |
Dates: |
Date | Event |
---|
June 2017 | Published | 22 March 2017 | Published Online | 24 December 2016 | Accepted |
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Projects: |
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PubMed ID: |
28327575 |
Web of Science ID: |
WOS:000402748700003 |
![](http://static.pubmed.gov/portal/portal3rc.fcgi/2745237/img/27842) |
Go to PubMed abstract |
URI: |
https://openaccess.sgul.ac.uk/id/eprint/109306 |
Publisher's version: |
https://doi.org/10.1038/ejhg.2017.32 |
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