Variants of Uncertain Significance
Babies with adrenoleukodystrophy (ALD) are neurologically normal at birth. Boys with ALD are at risk of developing adrenal insufficiency and/or inflammatory demyelinating brain lesions (cerebral ALD). Newborn screening has revolutionized the diagnosis and treatment of ALD, as it allows for the early identification of at-risk boys and life-saving interventions. These include initiating timely adrenal steroid replacement therapy following detection of adrenal insufficiency, and providing allogeneic hematopoietic stem cell transplantation (HSCT) as a means of treating cerebral ALD.
However, in the past five years, newborn screening has identified many boys and families with novel variants of ABCD1 who have no family history of any ALD-related disease symptoms, even with older relatives with the same variant. These novel variants are reported as “variants of uncertain significance (VUS)” on genetic testing reports. If a variant has not yet been linked to a specific disease, it is uncertain whether the variant is benign or pathogenic. However, a positive newborn screening result and referral to a medical specialist starts the process of follow-up and periodic testing for adrenal dysfunction and cerebral ALD by MRI.
The Grey Zone
The Grey Zone is a collaborative project between Team ALD of Amsterdam UMC and ALD Connect, aimed at advancing our understanding of variants of uncertain significance (VUS) associated with adrenoleukodystrophy (ALD) and determining their potential pathogenicity. If your genetic report concludes with ‘variant of uncertain significance,’ we are here to assist.
To learn more about this project, visit the Grey Zone projects page at ALD Connect or contact email@example.com. We will be happy to talk to you and connect you to the research team.
Watch Dr. Stephan Kemp’s presentation “The Grey Zone: My Genetic Test Comes Back ‘Variant of Uncertain Significance’ – Now What?” at the 2023 ALD Connect Annual Meeting and Patient Learning Academy.
Last modified | 2023-12-16