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Intronic variants in inborn errors of metabolism: Beyond the exome
Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availabilit...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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Frontiers Media S.A.
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763607/ https://www.ncbi.nlm.nih.gov/pubmed/36561316 http://dx.doi.org/10.3389/fgene.2022.1031495 |
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author | Hertzog, Ashley Selvanathan, Arthavan Farnsworth, Elizabeth Tchan, Michel Adams, Louisa Lewis, Katherine Tolun, Adviye Ayper Bennetts, Bruce Ho, Gladys Bhattacharya, Kaustuv |
author_facet | Hertzog, Ashley Selvanathan, Arthavan Farnsworth, Elizabeth Tchan, Michel Adams, Louisa Lewis, Katherine Tolun, Adviye Ayper Bennetts, Bruce Ho, Gladys Bhattacharya, Kaustuv |
author_sort | Hertzog, Ashley |
collection | PubMed |
description | Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availability of next generation sequencing, variants in non-coding regions are often considered when no causative exonic changes have been identified. There is still a lack of understanding of normal human variation in non-coding areas. As a result, potentially pathogenic non-coding variants are initially classified as variants of uncertain significance or are even overlooked during genomic analysis. In most cases where the phenotype is non-specific, clinical suspicion is not sufficient to warrant further exploration of these changes, partly due to the magnitude of non-coding variants identified. In contrast, inborn errors of metabolism (IEMs) are one group of genetic disorders where there is often high phenotypic specificity. The clinical and biochemical features seen often result in a narrow list of diagnostic possibilities. In this context, there have been numerous cases in which suspicion of a particular IEM led to the discovery of a variant in a non-coding region. We present four patients with IEMs where the molecular aetiology was identified within non-coding regions. Confirmation of the molecular diagnosis is often aided by the clinical and biochemical specificity associated with IEMs. Whilst the clinical severity associated with a non-coding variant can be difficult to predict, obtaining a molecular diagnosis is crucial as it ends diagnostic odysseys and assists in management. |
format | Online Article Text |
id | pubmed-9763607 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
spelling | pubmed-97636072022-12-21 Intronic variants in inborn errors of metabolism: Beyond the exome Hertzog, Ashley Selvanathan, Arthavan Farnsworth, Elizabeth Tchan, Michel Adams, Louisa Lewis, Katherine Tolun, Adviye Ayper Bennetts, Bruce Ho, Gladys Bhattacharya, Kaustuv Front Genet Genetics Non-coding regions are areas of the genome that do not directly encode protein and were initially thought to be of little biological relevance. However, subsequent identification of pathogenic variants in these regions indicates there are exceptions to this assertion. With the increasing availability of next generation sequencing, variants in non-coding regions are often considered when no causative exonic changes have been identified. There is still a lack of understanding of normal human variation in non-coding areas. As a result, potentially pathogenic non-coding variants are initially classified as variants of uncertain significance or are even overlooked during genomic analysis. In most cases where the phenotype is non-specific, clinical suspicion is not sufficient to warrant further exploration of these changes, partly due to the magnitude of non-coding variants identified. In contrast, inborn errors of metabolism (IEMs) are one group of genetic disorders where there is often high phenotypic specificity. The clinical and biochemical features seen often result in a narrow list of diagnostic possibilities. In this context, there have been numerous cases in which suspicion of a particular IEM led to the discovery of a variant in a non-coding region. We present four patients with IEMs where the molecular aetiology was identified within non-coding regions. Confirmation of the molecular diagnosis is often aided by the clinical and biochemical specificity associated with IEMs. Whilst the clinical severity associated with a non-coding variant can be difficult to predict, obtaining a molecular diagnosis is crucial as it ends diagnostic odysseys and assists in management. Frontiers Media S.A. 2022-12-06 /pmc/articles/PMC9763607/ /pubmed/36561316 http://dx.doi.org/10.3389/fgene.2022.1031495 Text en Copyright © 2022 Hertzog, Selvanathan, Farnsworth, Tchan, Adams, Lewis, Tolun, Bennetts, Ho and Bhattacharya. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
spellingShingle | Genetics Hertzog, Ashley Selvanathan, Arthavan Farnsworth, Elizabeth Tchan, Michel Adams, Louisa Lewis, Katherine Tolun, Adviye Ayper Bennetts, Bruce Ho, Gladys Bhattacharya, Kaustuv Intronic variants in inborn errors of metabolism: Beyond the exome |
title | Intronic variants in inborn errors of metabolism: Beyond the exome |
title_full | Intronic variants in inborn errors of metabolism: Beyond the exome |
title_fullStr | Intronic variants in inborn errors of metabolism: Beyond the exome |
title_full_unstemmed | Intronic variants in inborn errors of metabolism: Beyond the exome |
title_short | Intronic variants in inborn errors of metabolism: Beyond the exome |
title_sort | intronic variants in inborn errors of metabolism: beyond the exome |
topic | Genetics |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9763607/ https://www.ncbi.nlm.nih.gov/pubmed/36561316 http://dx.doi.org/10.3389/fgene.2022.1031495 |
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