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 by allowing early identification of boys at risk and life-saving interventions. These include the timely initiation of adrenal steroid replacement therapy after detection of adrenal insufficiency and the availability of allogeneic hematopoietic stem cell transplantation (HSCT) as a treatment for 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 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 test 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 specialist begins 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, that aims to improve our understanding of variants of uncertain significance (VUS) associated with adrenoleukodystrophy (ALD) and to determine their potential pathogenicity. If your genetic report concludes that a “variant of uncertain significance” has been identified in the ABCD1 gene, we are here to help.

To learn more about this project, visit the Grey Zone Projects page on the ALD Connect website or contact info@aldconnect.org. We would be happy to speak with you and put you in touch with 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 | 2024-06-25