Mosaic X-linked adrenoleukodystrophy in males identified by newborn screening and next-generation sequencing

Somatic mosaicism produces genetic differences between cells in an individual and is an underrecognized contributor to phenotypic variability. Precise understanding of the natural history of genetic diseases, therefore, requires detection and recognition of low-level mosaicism, which remains technically challenging, particularly for X-linked genes. Here, we identify six males with mosaic X-linked adrenoleukodystrophy (X-ALD), a neurometabolic peroxisomal disorder caused by pathogenic variants in ABCD1 that is currently included in 44 state newborn screening (NBS) programs, and estimate the incidence of somatic mosaicism. Of 227 males from 2 laboratories performing ABCD1 next-generation sequencing, 1.8% (4/227) had pathogenic or likely pathogenic ABCD1 variants that were mosaic. In one mosaic male individual, allele-specific measurements across multiple tissues demonstrated ABCD1 variant allele fractions ranging from 66 to 82%. Our findings have implications for the identification of X-ALD through NBS, and additional studies could provide insight into the pathogenesis and natural history of X-ALD.

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Publication Details

Journal
npj Genomic Medicine
Published
2025-05-09
DOI
https://doi.org/10.1038/s41525-025-00497-1
Primary Topic
Peroxisome Proliferator-Activated Receptors
Type
article
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article

Mosaic X-linked adrenoleukodystrophy in males identified by newborn screening and next-generation sequencing

Rebecca Tryon, Derek Wong, Lauren O’Grady, James T. Bennett et al.
npj Genomic Medicine
Peroxisome Proliferator-Activated Receptors
article

Mosaic X-linked adrenoleukodystrophy in males identified by newborn screening and next-generation sequencing

Rebecca Tryon, Derek Wong, Lauren O’Grady, James T. Bennett, Bianca Russell, Troy C. Lund, Barbara Hallinan, Erika Beckman, Inderneel Sahai, Renee Bend, Divya Vats, Dana M. Jensen, Michelle M. Morrow, Emily Shelkowitz, Ethan D. Sperry, Angela Sun, Monica Penon‐Portmann, Ahna M. Rabani, Minh Tu Pham, Paul Kruszka, Florian S Eichler, Erica Chan, Alexandra C Keefe, Kimberly Widmeyer, Natalie Y.T. Au
article en

Abstract

Somatic mosaicism produces genetic differences between cells in an individual and is an underrecognized contributor to phenotypic variability. Precise understanding of the natural history of genetic diseases, therefore, requires detection and recognition of low-level mosaicism, which remains technically challenging, particularly for X-linked genes. Here, we identify six males with mosaic X-linked adrenoleukodystrophy (X-ALD), a neurometabolic peroxisomal disorder caused by pathogenic variants in ABCD1 that is currently included in 44 state newborn screening (NBS) programs, and estimate the incidence of somatic mosaicism. Of 227 males from 2 laboratories performing ABCD1 next-generation sequencing, 1.8% (4/227) had pathogenic or likely pathogenic ABCD1 variants that were mosaic. In one mosaic male individual, allele-specific measurements across multiple tissues demonstrated ABCD1 variant allele fractions ranging from 66 to 82%. Our findings have implications for the identification of X-ALD through NBS, and additional studies could provide insight into the pathogenesis and natural history of X-ALD.

npj Genomic MedicineVol. 10(1)
Cincinnati Children's Hospital Medical Center (US), Seattle Children's Hospital (US), Fairview Health Services (US), Kaiser Permanente (US), Harvard University (US), University of California, Los Angeles (US), University of Washington (US), University of Washington Medical Center (US), Massachusetts General Hospital (US), Seattle Children's Hospital (US), University of Minnesota Medical Center (US), University of Cincinnati Medical Center (US)
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