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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
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.
0022-2593
Alhendi, Ahmed S.N.
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Lim, Derek
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Mckee, Shane
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Mcentagart, Meriel
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Tatton-Brown, Katriona
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Temple, I Karen
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Davies, Justin H.
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Mackay, Deborah J.G.
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Alhendi, Ahmed S.N.
2b38755a-486e-4944-94a6-dc1ff7105efa
Lim, Derek
e1acfb9c-6481-4902-ba7e-768bdd8cf2c1
Mckee, Shane
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Mcentagart, Meriel
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Tatton-Brown, Katriona
f0f1d61f-33fd-4796-8c18-a2f67cb19700
Temple, I Karen
d63e7c66-9fb0-46c8-855d-ee2607e6c226
Davies, Justin H.
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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. (doi:10.1136/jmedgenet-2021-107699).

Record type: Article

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.

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alhendi21accepted-ms - Accepted Manuscript
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Accepted/In Press date: 6 May 2021
e-pub ahead of print date: 16 June 2021

Identifiers

Local EPrints ID: 449912
URI: http://eprints.soton.ac.uk/id/eprint/449912
ISSN: 0022-2593
PURE UUID: 3e2070ff-06e5-4ee0-9df0-1b43cace3de2
ORCID for I Karen Temple: ORCID iD orcid.org/0000-0002-6045-1781
ORCID for Deborah J.G. Mackay: ORCID iD orcid.org/0000-0003-3088-4401

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Date deposited: 25 Jun 2021 16:30
Last modified: 26 Jun 2021 01:36

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Contributors

Author: Derek Lim
Author: Shane Mckee
Author: Meriel Mcentagart
Author: Katriona Tatton-Brown
Author: I Karen Temple ORCID iD

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