Early-onset Wilson disease caused by ATP7B exon skipping associated with intronic variant.

Cold Spring Harbor Molecular Case Studies
Daniel C KoboldtRichard K Wilson

Abstract

Wilson disease is a medically actionable rare autosomal recessive disorder of defective copper excretion caused by mutations in ATP7B, one of two highly evolutionarily conserved copper-transporting ATPases. Hundreds of disease-causing variants in ATP7B have been reported to public databases; more than half of these are missense changes, and a significant proportion are presumed unequivocal loss-of-function variants (nonsense, frameshift, and canonical splice site). Current molecular genetic testing includes sequencing all coding exons (±10 bp) as well as deletion/duplication testing, with reported sensitivity of >98%. We report a proband from a consanguineous family with a biochemical phenotype consistent with early-onset Wilson disease who tested negative on conventional molecular genetic testing. Using a combination of whole-genome sequencing and transcriptome sequencing, we found that the proband's disease is due to skipping of exons 6-7 of the ATP7B gene associated with a novel intronic variant (NM_000053.4:c.1947-19T > A) that alters a putative splicing enhancer element. This variant was also homozygous in the proband's younger sister, whose subsequent clinical evaluations revealed biochemical evidence of Wilson disease. O...Continue Reading

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Methods Mentioned

BETA
exome sequencing
biopsy
RNA-seq
X-ray
genotyping
Genome Sequencing

Software Mentioned

gnomAD
VarScan
PolyPhen
- aligner
Human Splicing Finder
RNA
STAR
HTSeq
GERP
Integrative Genomics Viewer

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