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Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders
Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders
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.
1018-4813
669-679
Pagnamenta, Alistair T.
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Murakami, Yoshiko
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Taylor, John M.
a42e74b2-35c6-4c62-b171-0c438e81b488
Anzilotti, Consuelo
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Howard, Malcolm F.
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Miller, Venessa
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Johnson, Diana S.
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Tadros, Shereen
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Mansour, Sahar
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Temple, I. Karen
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Firth, Rachel
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Rosser, Elisabeth
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Harrison, Rachel E.
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Kerr, Bronwen
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Popitsch, Niko
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Kinoshita, Taroh
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Taylor, Jenny C.
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Kini, Usha
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Pagnamenta, Alistair T.
0ea15db3-9da9-4e3a-b1a2-8f28380936d2
Murakami, Yoshiko
33c1e6fe-b1ce-468d-b837-8ae1e2614405
Taylor, John M.
a42e74b2-35c6-4c62-b171-0c438e81b488
Anzilotti, Consuelo
5862dd11-b066-49e6-b0ca-2e250552d022
Howard, Malcolm F.
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Miller, Venessa
25a2967b-7668-40c1-8a6d-1a116841f16e
Johnson, Diana S.
e086c2cf-2064-4b00-a692-b37984b4fc2a
Tadros, Shereen
7c223479-c65e-4110-b52f-4146299afb96
Mansour, Sahar
fcece354-b435-46fb-8acf-184dad0ed4c2
Temple, I. Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Firth, Rachel
bd1644e0-3b88-48b5-9827-edcd191d8e6d
Rosser, Elisabeth
44dd1485-20cb-4f27-ba1f-7c47e06d926c
Harrison, Rachel E.
4f41de86-cbcd-4929-bfbb-6f3422088f32
Kerr, Bronwen
a553872f-779d-4123-9974-55a2f32e9f79
Popitsch, Niko
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Kinoshita, Taroh
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Taylor, Jenny C.
52b015d8-7a23-45c1-a6aa-80df9c1b873c
Kini, Usha
f54f7e90-64be-43f2-adaf-af87c4dcd4ce

Pagnamenta, Alistair T., Murakami, Yoshiko, Taylor, John M., Anzilotti, Consuelo, Howard, Malcolm F., Miller, Venessa, Johnson, Diana S., Tadros, Shereen, Mansour, Sahar, Temple, I. Karen, Firth, Rachel, Rosser, Elisabeth, Harrison, Rachel E., Kerr, Bronwen, Popitsch, Niko, Kinoshita, Taroh, Taylor, Jenny C. and Kini, Usha (2017) Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders. European Journal of Human Genetics, 25 (6), 669-679. (doi:10.1038/ejhg.2017.32).

Record type: Article

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.

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Accepted/In Press date: 24 December 2016
e-pub ahead of print date: 22 March 2017
Published date: June 2017
Organisations: Human Development & Health

Identifiers

Local EPrints ID: 407611
URI: http://eprints.soton.ac.uk/id/eprint/407611
ISSN: 1018-4813
PURE UUID: 7d2c3607-c4e9-48b3-9f77-69fad1ef971d
ORCID for I. Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781

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Date deposited: 16 Apr 2017 17:00
Last modified: 16 Mar 2024 05:11

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Contributors

Author: Alistair T. Pagnamenta
Author: Yoshiko Murakami
Author: John M. Taylor
Author: Consuelo Anzilotti
Author: Malcolm F. Howard
Author: Venessa Miller
Author: Diana S. Johnson
Author: Shereen Tadros
Author: Sahar Mansour
Author: I. Karen Temple ORCID iD
Author: Rachel Firth
Author: Elisabeth Rosser
Author: Rachel E. Harrison
Author: Bronwen Kerr
Author: Niko Popitsch
Author: Taroh Kinoshita
Author: Jenny C. Taylor
Author: Usha Kini

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