Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study
Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study
Background Silver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.
Methods To determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.
Results In 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4.
Conclusion WGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.
genetics, genomics, medical
613-622
Alhendi, Ahmed S.N.
2b38755a-486e-4944-94a6-dc1ff7105efa
Lim, Derek
e1acfb9c-6481-4902-ba7e-768bdd8cf2c1
Mckee, Shane
697d9bc8-c8dd-43dd-b829-1f4bcf0c2c82
Mcentagart, Meriel
4934e0c0-a279-4603-a3a3-8f364e82fbea
Tatton-Brown, Katriona
f0f1d61f-33fd-4796-8c18-a2f67cb19700
Temple, I Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Davies, Justin H.
9f18fcad-f488-4c72-ac23-c154995443a9
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
16 June 2021
Alhendi, Ahmed S.N.
2b38755a-486e-4944-94a6-dc1ff7105efa
Lim, Derek
e1acfb9c-6481-4902-ba7e-768bdd8cf2c1
Mckee, Shane
697d9bc8-c8dd-43dd-b829-1f4bcf0c2c82
Mcentagart, Meriel
4934e0c0-a279-4603-a3a3-8f364e82fbea
Tatton-Brown, Katriona
f0f1d61f-33fd-4796-8c18-a2f67cb19700
Temple, I Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Davies, Justin H.
9f18fcad-f488-4c72-ac23-c154995443a9
Mackay, Deborah J.G.
588a653e-9785-4a00-be71-4e547850ee4a
Alhendi, Ahmed S.N., Lim, Derek, Mckee, Shane, Mcentagart, Meriel, Tatton-Brown, Katriona, Temple, I Karen, Davies, Justin H. and Mackay, Deborah J.G.
(2021)
Whole-genome analysis as a diagnostic tool for patients referred for diagnosis of Silver-Russell syndrome: a real-world study.
Journal of Medical Genetics, 59 (6), .
(doi:10.1136/jmedgenet-2021-107699).
Abstract
Background Silver-Russell syndrome (SRS) is an imprinting disorder characterised by prenatal and postnatal growth restriction, but its clinical features are non-specific and its differential diagnosis is broad. Known molecular causes of SRS include imprinting disturbance, single nucleotide variant (SNV), CNV or UPD affecting several genes; however, up to 40% of individuals with a clinical diagnosis of SRS currently receive no positive molecular diagnosis.
Methods To determine whether whole-genome sequencing (WGS) could uncover pathogenic variants missed by current molecular testing, we analysed data of 72 participants recruited to the 100,000 Genomes Project within the clinical category of SRS.
Results In 20 participants (27% of the cohort) we identified genetic variants plausibly accounting for SRS. Coding SNVs were identified in genes including CDKN1C, IGF2, IGF1R and ORC1. Maternal-effect variants were found in mothers of five participants, including two participants with imprinting disturbance and one with multilocus imprinting disorder. Two regions of homozygosity were suggestive of UPD involving imprinted regions implicated in SRS and Temple syndrome, and three plausibly pathogenic CNVs were found, including a paternal deletion of PLAGL1. In 48 participants with no plausible pathogenic variant, unbiased analysis of SNVs detected a potential association with STX4.
Conclusion WGS analysis can detect UPD, CNV and SNV and is potentially a valuable addition to diagnosis of SRS and related growth-restricting disorders.
Text
alhendi21accepted-ms
- Accepted Manuscript
More information
Accepted/In Press date: 6 May 2021
e-pub ahead of print date: 16 June 2021
Published date: 16 June 2021
Additional Information:
Funding Information:
Funding ASNA was funded by the Child Growth Foundation, UK. IKT is supported by the NIHR Biomedical Research Centre (BRC), Southampton. The Wellcome Trust, Cancer Research UK and the Medical Research Council funded the research infrastructure. The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England.
Publisher Copyright:
© Author(s) (or their employer(s)) 2022.
Copyright:
Copyright 2022 Elsevier B.V., All rights reserved.
Keywords:
genetics, genomics, medical
Identifiers
Local EPrints ID: 449912
URI: http://eprints.soton.ac.uk/id/eprint/449912
ISSN: 0022-2593
PURE UUID: 3e2070ff-06e5-4ee0-9df0-1b43cace3de2
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Date deposited: 25 Jun 2021 16:30
Last modified: 17 Mar 2024 02:48
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Contributors
Author:
Ahmed S.N. Alhendi
Author:
Derek Lim
Author:
Shane Mckee
Author:
Meriel Mcentagart
Author:
Katriona Tatton-Brown
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