Phenotypes of undiagnosed adults with actionable OTC and GLA variants

• Published in: HGG advances 2023-10, Vol.4 (4), p.100226-100226, Article 100226
• Main Authors: 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.
• Format: Article
• Language: English
• Subjects: Fabry disease; Genomic newborn screening; Genomic return of results; Genotype first approach; Hospital biobank; Inherited metabolic disorder; Ornithine transcarbamylase (OTC) deficiency; Penetrance; Secondary findings; Variable expressivity
• ISSN: 2666-2477; 2666-2477
• DOI: 10.1016/j.xhgg.2023.100226

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. A genotype-first approach can identify individuals at risk for undiagnosed inherited metabolic disorders. In this study, approximately 1 in 19,100 biobank participants harbored undiagnosed pathogenic and likely pathogenic variants associated with Fabry disease and ornithine transcarbamylase deficiency. Most individuals had signs of attenuated disease.