Early-onset Wilson disease caused by ATP7B exon skipping associated with intronic variant
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 t...
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Veröffentlicht in: | Cold Spring Harbor molecular case studies 2020-06, Vol.6 (3), p.a005306 |
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Sprache: | eng |
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Zusammenfassung: | 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. Our work adds to emerging evidence that
ATP7B
exon skipping from deep intronic variants outside typical splice junctions is an important mechanism of Wilson disease; the variants responsible may elude standard genetic testing. |
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ISSN: | 2373-2865 2373-2873 |
DOI: | 10.1101/mcs.a005306 |