Phenotypes of undiagnosed adults with actionable OTC and GLA variants
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
Affiliations
Jessica I. Gold
Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia; Philadelphia, PA, USA
Sarina Madhavan
Harvard Medical School, Boston, MA, USA; Harvard Business School, Cambridge, MA, USA
Joseph Park
Department of Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Hana Zouk
Harvard Medical School, Boston, MA, USA; Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine, Cambridge MA, USA; Department of Pathology, Massachusetts General Hospital, Boston, MA, USA
Emma Perez
Mass General Brigham Personalized Medicine, Cambridge MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA
Alanna Strong
Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia; Philadelphia, PA, USA; Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA; Center for Applied Genomics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Theodore G. Drivas
Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
Amel Karaa
Massachusetts General Hospital for Children, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA
Marc Yudkoff
Division of Human Genetics, Department of Pediatrics, Children’s Hospital of Philadelphia; Philadelphia, PA, USA; Division of Human Genetics, Children’s Hospital of Philadelphia, Philadelphia, PA, USA
Daniel Rader
Department of Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Division of Translational Medicine and Human Genetics, Department of Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
Robert C. Green
Harvard Medical School, Boston, MA, USA; Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Broad Institute, Boston, MA, USA; Ariadne Labs, Boston, MA, USA
Nina B. Gold
Massachusetts General Hospital for Children, Boston, MA, USA; Department of Pediatrics, Harvard Medical School, Boston, MA, USA; Corresponding author
Summary: 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.
