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A founder UMOD variant is a common cause of hereditary nephropathy in the British population
BACKGROUND: Monogenic disorders are estimated to account for 10%–12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin (UMOD) variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant. ME...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BMJ Publishing Group
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086494/ https://www.ncbi.nlm.nih.gov/pubmed/36038257 http://dx.doi.org/10.1136/jmg-2022-108704 |
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author | Valluru, Manoj K Chung, Noelle KX Gilchrist, Mark Butland, Laura Cook, Jackie Takou, Anna Dixit, Abhijit Weedon, Michael N Ong, Albert C M |
author_facet | Valluru, Manoj K Chung, Noelle KX Gilchrist, Mark Butland, Laura Cook, Jackie Takou, Anna Dixit, Abhijit Weedon, Michael N Ong, Albert C M |
author_sort | Valluru, Manoj K |
collection | PubMed |
description | BACKGROUND: Monogenic disorders are estimated to account for 10%–12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin (UMOD) variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant. METHODS: Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of UMOD c.278_289delTCTGCCCCGAAG insCCGCCTCCT. RESULTS: A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the UMOD variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype. CONCLUSION: Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry. |
format | Online Article Text |
id | pubmed-10086494 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | BMJ Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-100864942023-04-12 A founder UMOD variant is a common cause of hereditary nephropathy in the British population Valluru, Manoj K Chung, Noelle KX Gilchrist, Mark Butland, Laura Cook, Jackie Takou, Anna Dixit, Abhijit Weedon, Michael N Ong, Albert C M J Med Genet Population Genetics BACKGROUND: Monogenic disorders are estimated to account for 10%–12% of patients with kidney failure. We report the unexpected finding of an unusual uromodulin (UMOD) variant in multiple pedigrees within the British population and demonstrate a shared haplotype indicative of an ancestral variant. METHODS: Probands from 12 apparently unrelated pedigrees with a family history of kidney failure within a geographically contiguous UK region were shown to be heterozygous for a pathogenic variant of UMOD c.278_289delTCTGCCCCGAAG insCCGCCTCCT. RESULTS: A total of 88 clinically affected individuals were identified, all born in the UK and of white British ethnicity. 20 other individuals with the variant were identified in the UK 100,000 Genomes (100K) Project and 9 from UK Biobank (UKBB). A common extended haplotype was present in 5 of the UKBB individuals who underwent genome sequencing which was only present in <1 in 5000 of UKBB controls. Significantly, rare variants (<1 in 250 general population) identified within 1 Mb of the UMOD variant by genome sequencing were detected in all of the 100K individuals, indicative of an extended shared haplotype. CONCLUSION: Our data confirm a likely founder UMOD variant with a wide geographical distribution within the UK. It should be suspected in cases of unexplained familial nephropathy presenting in patients of white British ancestry. BMJ Publishing Group 2023-04 2022-08-29 /pmc/articles/PMC10086494/ /pubmed/36038257 http://dx.doi.org/10.1136/jmg-2022-108704 Text en © Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY. Published by BMJ. https://creativecommons.org/licenses/by/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Population Genetics Valluru, Manoj K Chung, Noelle KX Gilchrist, Mark Butland, Laura Cook, Jackie Takou, Anna Dixit, Abhijit Weedon, Michael N Ong, Albert C M A founder UMOD variant is a common cause of hereditary nephropathy in the British population |
title | A founder UMOD variant is a common cause of hereditary nephropathy in the British population |
title_full | A founder UMOD variant is a common cause of hereditary nephropathy in the British population |
title_fullStr | A founder UMOD variant is a common cause of hereditary nephropathy in the British population |
title_full_unstemmed | A founder UMOD variant is a common cause of hereditary nephropathy in the British population |
title_short | A founder UMOD variant is a common cause of hereditary nephropathy in the British population |
title_sort | founder umod variant is a common cause of hereditary nephropathy in the british population |
topic | Population Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10086494/ https://www.ncbi.nlm.nih.gov/pubmed/36038257 http://dx.doi.org/10.1136/jmg-2022-108704 |
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