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Phenotypes of undiagnosed adults with actionable OTC and GLA variants
Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and m...
Autores principales: | , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Elsevier
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10428110/ https://www.ncbi.nlm.nih.gov/pubmed/37593415 http://dx.doi.org/10.1016/j.xhgg.2023.100226 |
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author | Gold, Jessica I. Madhavan, Sarina Park, Joseph Zouk, Hana Perez, Emma Strong, Alanna Drivas, Theodore G. Karaa, Amel Yudkoff, Marc Rader, Daniel Green, Robert C. Gold, Nina B. |
author_facet | Gold, Jessica I. Madhavan, Sarina Park, Joseph Zouk, Hana Perez, Emma Strong, Alanna Drivas, Theodore G. Karaa, Amel Yudkoff, Marc Rader, Daniel Green, Robert C. Gold, Nina B. |
author_sort | Gold, Jessica I. |
collection | PubMed |
description | Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care. |
format | Online Article Text |
id | pubmed-10428110 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Elsevier |
record_format | MEDLINE/PubMed |
spelling | pubmed-104281102023-08-17 Phenotypes of undiagnosed adults with actionable OTC and GLA variants Gold, Jessica I. Madhavan, Sarina Park, Joseph Zouk, Hana Perez, Emma Strong, Alanna Drivas, Theodore G. Karaa, Amel Yudkoff, Marc Rader, Daniel Green, Robert C. Gold, Nina B. HGG Adv Report Inherited metabolic disorders (IMDs) are variably expressive, complicating identification of affected individuals. A genotype-first approach can identify individuals at risk for morbidity and mortality from undiagnosed IMDs and can lead to protocols that improve clinical detection, counseling, and management. Using data from 57,340 participants in two hospital biobanks, we assessed the frequency and phenotypes of individuals with pathogenic/likely pathogenic variants (PLPVs) in two IMD genes: GLA, associated with Fabry disease, and OTC, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in GLA or OTC. We identified three individuals (2 male, 1 female) with PLPVs in GLA, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in OTC, two of whom were undiagnosed. All three individuals with PLPVs in GLA (100%) had symptoms suggestive of mild Fabry disease, and one individual (14.2%) had an ischemic stroke at age 33, likely indicating the presence of classic disease. No individuals with PLPVs in OTC had documented hyperammonemia despite exposure to catabolic states, but all (100%) had chronic symptoms suggestive of attenuated disease, including mood disorders and migraines. Our findings suggest that GLA and OTC variants identified via a genotype-first approach are of high penetrance and that population screening of these genes can be used to facilitate stepwise phenotyping and appropriate care. Elsevier 2023-07-29 /pmc/articles/PMC10428110/ /pubmed/37593415 http://dx.doi.org/10.1016/j.xhgg.2023.100226 Text en © 2023 The Author(s) https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). |
spellingShingle | Report Gold, Jessica I. Madhavan, Sarina Park, Joseph Zouk, Hana Perez, Emma Strong, Alanna Drivas, Theodore G. Karaa, Amel Yudkoff, Marc Rader, Daniel Green, Robert C. Gold, Nina B. Phenotypes of undiagnosed adults with actionable OTC and GLA variants |
title | Phenotypes of undiagnosed adults with actionable OTC and GLA variants |
title_full | Phenotypes of undiagnosed adults with actionable OTC and GLA variants |
title_fullStr | Phenotypes of undiagnosed adults with actionable OTC and GLA variants |
title_full_unstemmed | Phenotypes of undiagnosed adults with actionable OTC and GLA variants |
title_short | Phenotypes of undiagnosed adults with actionable OTC and GLA variants |
title_sort | phenotypes of undiagnosed adults with actionable otc and gla variants |
topic | Report |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10428110/ https://www.ncbi.nlm.nih.gov/pubmed/37593415 http://dx.doi.org/10.1016/j.xhgg.2023.100226 |
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