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Papers of the Week

Papers: 19 Aug 2023 - 25 Aug 2023

Basic Science

Genetics, Human Studies, Molecular/Cellular, Neurobiology


2023 Oct 12





Phenotypes of undiagnosed adults with actionable and variants.


Gold JI, Madhavan S, Park J, Zouk H, Perez E, Strong A, Drivas TG, Karaa A, Yudkoff M, Rader D, , , Green RC, Gold NB


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: , associated with Fabry disease, and , associated with ornithine transcarbamylase deficiency. Approximately 1 in 19,100 participants harbored an undiagnosed PLPV in or . We identified three individuals (2 male, 1 female) with PLPVs in , all of whom were undiagnosed, and three individuals (3 female) with PLPVs in , two of whom were undiagnosed. All three individuals with PLPVs in (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 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 and 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.