Multi-Omic Approach to Identify Phenotypic Modifiers Underlying Cerebral Demyelination in X-Linked Adrenoleukodystrophy

Frontiers in Cell and Developmental Biology
P. A. RichmondClara D M van Karnebeek

Abstract

X-linked adrenoleukodystrophy (ALD) is a peroxisomal metabolic disorder with a highly complex clinical presentation. ALD is caused by mutations in the ABCD1 gene, and is characterized by the accumulation of very long-chain fatty acids in plasma and tissues. Disease-causing mutations are 'loss of function' mutations, with no prognostic value with respect to the clinical outcome of an individual. All male patients with ALD develop spinal cord disease and a peripheral neuropathy in adulthood, although age of onset is highly variable. However, the lifetime prevalence to develop progressive white matter lesions, termed cerebral ALD (CALD), is only about 60%. Early identification of transition to CALD is critical since it can be halted by allogeneic hematopoietic stem cell therapy only in an early stage. The primary goal of this study is to identify molecular markers which may be prognostic of cerebral demyelination from a simple blood sample, with the hope that blood-based assays can replace the current protocols for diagnosis. We collected six well-characterized brother pairs affected by ALD and discordant for the presence of CALD and performed multi-omic profiling of blood samples including genome, epigenome, transcriptome, metabo...Continue Reading

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Citations

Dec 30, 2020·Journal of Inherited Metabolic Disease·Roberto MontoroMarc Engelen
Nov 29, 2020·Molecular Genetics and Metabolism·Clara D M van KarnebeekStephan Kemp
May 1, 2021·International Journal of Molecular Sciences·Patrycja JuchniewiczJoanna Jakóbkiewicz-Banecka

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Methods Mentioned

BETA
Whole Genome Sequencing
genotyping
RNA-seq

Software Mentioned

GEMINI
edgeR
Centrifuge
Limma
GATK HaplotypeCaller
DeepVariant
custom
Intervene
CALD
variancePartition

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