Jessica I Gold, Sarina Madhavan, Joseph Park, Hana Zouk, Emma Perez, Alanna Strong, Theodore G Drivas, Amel Karaa, Marc Yudkoff, Daniel Rader, Robert C Green, Nina B Gold
{"title":"具有可操作OTC和GLA变体的未确诊成年人的表型。","authors":"Jessica I Gold, Sarina Madhavan, Joseph Park, Hana Zouk, Emma Perez, Alanna Strong, Theodore G Drivas, Amel Karaa, Marc Yudkoff, Daniel Rader, Robert C Green, Nina B Gold","doi":"10.1016/j.xhgg.2023.100226","DOIUrl":null,"url":null,"abstract":"<p><p>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: <i>GLA</i>, associated with Fabry disease, and <i>OTC</i>, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in <i>GLA</i> or <i>OTC</i>. We identified three individuals (2 male, 1 female) with PLPVs in <i>GLA</i>, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in <i>OTC</i>, two of whom were undiagnosed. All three individuals with PLPVs in <i>GLA</i> (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 <i>OTC</i> 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 <i>GLA</i> and <i>OTC</i> 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.</p>","PeriodicalId":34530,"journal":{"name":"HGG Advances","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2023-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/94/main.PMC10428110.pdf","citationCount":"0","resultStr":"{\"title\":\"Phenotypes of undiagnosed adults with actionable <i>OTC</i> and <i>GLA</i> variants.\",\"authors\":\"Jessica I Gold, Sarina Madhavan, Joseph Park, Hana Zouk, Emma Perez, Alanna Strong, Theodore G Drivas, Amel Karaa, Marc Yudkoff, Daniel Rader, Robert C Green, Nina B Gold\",\"doi\":\"10.1016/j.xhgg.2023.100226\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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: <i>GLA</i>, associated with Fabry disease, and <i>OTC</i>, associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in <i>GLA</i> or <i>OTC</i>. We identified three individuals (2 male, 1 female) with PLPVs in <i>GLA</i>, all of whom were undiagnosed, and three individuals (3 female) with PLPVs in <i>OTC</i>, two of whom were undiagnosed. All three individuals with PLPVs in <i>GLA</i> (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 <i>OTC</i> 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 <i>GLA</i> and <i>OTC</i> 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.</p>\",\"PeriodicalId\":34530,\"journal\":{\"name\":\"HGG Advances\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2023-07-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://ftp.ncbi.nlm.nih.gov/pub/pmc/oa_pdf/c0/94/main.PMC10428110.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"HGG Advances\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xhgg.2023.100226\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2023/10/12 0:00:00\",\"PubModel\":\"eCollection\",\"JCR\":\"Q2\",\"JCRName\":\"GENETICS & HEREDITY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"HGG Advances","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xhgg.2023.100226","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2023/10/12 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"GENETICS & HEREDITY","Score":null,"Total":0}
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 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.