A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project)
A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project)
Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior–Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.
9369
Leggatt, Gary
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Cheng, Guo
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Narain, Sumit
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Briseno-Roa, Luis
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Annereau, Jean-Philippe
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Gast, Christine
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Gilbert, Rodney
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Ennis, Sarah
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Genomics England Research Consortium
9 June 2023
Leggatt, Gary
546eb2be-3056-4e1b-bbef-66b6313280af
Cheng, Guo
fdfb3e03-f185-49b1-9c53-05b93bb6c8d0
Narain, Sumit
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Briseno-Roa, Luis
6568fd5f-7b91-465d-9e61-0a223c0e900a
Annereau, Jean-Philippe
7e272d46-d717-442d-ae94-63c0b2a7e6fe
Gast, Christine
7719218f-9b52-4126-8355-51361095797c
Gilbert, Rodney
c69c5b99-2a15-4502-acd8-36b254d42601
Ennis, Sarah
7b57f188-9d91-4beb-b217-09856146f1e9
Genomics England Research Consortium
(2023)
A genotype-to-phenotype approach suggests under-reporting of single nucleotide variants in nephrocystin-1 (NPHP1) related disease (UK 100,000 Genomes Project).
Scientific Reports, 13 (1), , [9369].
(doi:10.1038/s41598-023-32169-4).
Abstract
Autosomal recessive whole gene deletions of nephrocystin-1 (NPHP1) result in abnormal structure and function of the primary cilia. These deletions can result in a tubulointerstitial kidney disease known as nephronophthisis and retinal (Senior–Løken syndrome) and neurological (Joubert syndrome) diseases. Nephronophthisis is a common cause of end-stage kidney disease (ESKD) in children and up to 1% of adult onset ESKD. Single nucleotide variants (SNVs) and small insertions and deletions (Indels) have been less well characterised. We used a gene pathogenicity scoring system (GenePy) and a genotype-to-phenotype approach on individuals recruited to the UK Genomics England (GEL) 100,000 Genomes Project (100kGP) (n = 78,050). This approach identified all participants with NPHP1-related diseases reported by NHS Genomics Medical Centres and an additional eight participants. Extreme NPHP1 gene scores, often underpinned by clear recessive inheritance, were observed in patients from diverse recruitment categories, including cancer, suggesting the possibility of a more widespread disease than previously appreciated. In total, ten participants had homozygous CNV deletions with eight homozygous or compound heterozygous with SNVs. Our data also reveals strong in-silico evidence that approximately 44% of NPHP1 related disease may be due to SNVs with AlphaFold structural modelling evidence for a significant impact on protein structure. This study suggests historical under-reporting of SNVS in NPHP1 related diseases compared with CNVs.
Text
Manuscript Genotype-phenotype associations in NPHP1 010323 CLEAN
- Accepted Manuscript
Text
s41598-023-32169-4
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More information
Accepted/In Press date: 23 March 2023
e-pub ahead of print date: 9 June 2023
Published date: 9 June 2023
Additional Information:
Funding Information:
This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. David Rinaldo for his helpful advice with the modelling using Maestro & BioLuminate suite (Schrodinger, NY). Analyses of copy number variants in NPHP1 were initially performed by Dr Guillermo del Angel, Alexion Pharmaceuticals Inc. This study was supported by the National Institute for Health Research (NIHR) Southampton Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Funding Information:
This research was made possible through access to the data and findings generated by the 100,000 Genomes Project. The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK and the Medical Research Council have also funded research infrastructure. The 100,000 Genomes Project uses data provided by patients and collected by the National Health Service as part of their care and support. David Rinaldo for his helpful advice with the modelling using Maestro & BioLuminate suite (Schrodinger, NY). Analyses of copy number variants in NPHP1 were initially performed by Dr Guillermo del Angel, Alexion Pharmaceuticals Inc. This study was supported by the National Institute for Health Research (NIHR) Southampton Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.
Publisher Copyright:
© 2023, The Author(s).
Identifiers
Local EPrints ID: 477783
URI: http://eprints.soton.ac.uk/id/eprint/477783
ISSN: 2045-2322
PURE UUID: 7e37219c-4b5d-4b9d-817f-6550da9afc9f
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Date deposited: 14 Jun 2023 16:43
Last modified: 18 Apr 2024 01:54
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Contributors
Author:
Gary Leggatt
Author:
Guo Cheng
Author:
Sumit Narain
Author:
Luis Briseno-Roa
Author:
Jean-Philippe Annereau
Author:
Christine Gast
Author:
Rodney Gilbert
Corporate Author: Genomics England Research Consortium
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