title: A hemizygous SCO2 mutation in an early onset rapidly progressive, fatal cardiomyopathy.
abstract: Mutations in SCO2, a metallochaperone involved in mitochondrial copper delivery, are associated with early onset, fatal hypertrophic cardiomyopathy. All reported patients carry at least one copy of the common 1541G>A (E140K) mutation. Whereas patients with one copy of the E140K allele, in combination with a more deleterious mutation, follow a severe clinical course, patients homozygous for the E140K mutation have a delayed onset of disease and a more prolonged survival. Here, we have investigated a patient who appeared homozygous for the common 1541G>A mutation based on DNA sequencing and restriction enzyme analysis of a PCR product, yet presented with early onset, severe cardiomyopathy. Restriction enzyme analysis of parental DNA revealed that the mother was heterozygous for 1541G>A, while the father was homozygous wild-type. The patient showed biparental inheritance for microsatellite markers spanning the length of chromosome 22, making isodisomy unlikely. Sequencing of several single nucleotide polymorphisms within the 5'-UTR, intron and single exon of the SCO2 gene was uninformative; however, a 16 bp deletion within the intron was present in the patient and the mother, but not the father. Restriction enzyme analysis confirmed that the mother was heterozygous and that the patient was hemizygous for the deletion. Southern blot, Northern blot, and FISH analyses were consistent with the de novo deletion of one allele of SCO2 in the patient. This is the first report of hemizygosity in a SCO2 patient. The patient phenotype underscores the strikingly similar clinical course in all patients with one copy of the E140K allele. Examination of both patient and parental genotypes by thorough molecular analyses can reveal information with important implications for genetic counseling.
authors.affiliation: Department of Pathology and Laboratory Medicine, Children's & Women's Health Centre of British Columbia, University of British Columbia, Vancouver, BC, Canada V6H 3V4. sleary@po-box.mcgill.ca <sleary@po-box.mcgill.ca>
authors.forename: Scot C
authors.initials: SC
authors.lastname: Leary
authors.forename: Andre
authors.initials: A
authors.lastname: Mattman
authors.forename: Timothy
authors.initials: T
authors.lastname: Wai
authors.forename: David C
authors.initials: DC
authors.lastname: Koehn
authors.forename: Lorne A
authors.initials: LA
authors.lastname: Clarke
authors.forename: Suzanne
authors.initials: S
authors.lastname: Chan
authors.forename: Brenda
authors.initials: B
authors.lastname: Lomax
authors.forename: Patrice
authors.initials: P
authors.lastname: Eydoux
authors.forename: Hilary D
authors.initials: HD
authors.lastname: Vallance
authors.forename: Eric A
authors.initials: EA
authors.lastname: Shoubridge
mesh_terms: D009202:Cardiomyopathies / Q000175:diagnosis* / Q000235:genetics; D002352:Carrier Proteins; D004252:DNA Mutational Analysis; D017809:Fatal Outcome; D006801:Humans; D007223:Infant; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D009154:Mutation; D009693:Nucleic Acid Hybridization; D011506:Proteins / Q000235:genetics*; D017384:Sequence Deletion
chemical_list: D002352:Carrier Proteins; D024101:Mitochondrial Proteins; D018832:Molecular Chaperones; D011506:Proteins; C400285:SCO2 protein, human