Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis.
Mitochondrial DNA (mtDNA) depletion syndrome encompasses a heterogeneous group of disorders characterized by a reduction in the mtDNA copy number. We identified two patients with clinical presentations consistent with mtDNA depletion syndrome (MDS), who were subsequently found to have apparently homozygous point mutations in TYMP and DGUOK, two of the nine nuclear genes commonly associated with these disorders. Further sequence analyses of parents indicated that in each case only one parent; the mother of the first and the father of the second, was a heterozygous carrier of the mutation identified in the affected child. The presence of underlying deletions was ruled out by use of a custom target array comparative genomic hybridization (CGH) platform. A high-density single-nucleotide polymorphism (SNP) array analysis revealed that the first patient had a region of copy-neutral absence of heterozygosity (AOH) consistent with segmental isodisomy for an 11.3 Mb region at the long-arm terminus of chromosome 22 (including the TYMP gene), and the second patient had results consistent with complete isodisomy of chromosome 2 (where the DGUOK gene is located). The combined sequencing, array CGH and SNP array approaches have demonstrated the first cases of MDS due to uniparental isodisomy. This diagnostic scenario also demonstrates the necessity of comprehensive examination of the underlying molecular defects of an apparently homozygous mutation in order to provide patients and their families with the most accurate molecular diagnosis and genetic counseling.
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
Ganka V
GV
Douglas
Joanna
J
Wiszniewska
Mark H
MH
Lipson
David R
DR
Witt
Taryn
T
McDowell
Mara
M
Sifry-Platt
Michio
M
Hirano
William J
WJ
Craigen
Lee-Jun C
LJ
Wong
D000328:Adult; D001483:Base Sequence; D002889:Chromosomes, Human, Pair 2; D002892:Chromosomes, Human, Pair 22; D055028:Comparative Genomic Hybridization; D004272:DNA, Mitochondrial / Q000235:genetics*; D017809:Fatal Outcome; D005260:Female; D005500:Follow-Up Studies; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D028361:Mitochondrial Diseases / Q000235:genetics*; D009154:Mutation; D010375:Pedigree; D020641:Polymorphism, Single Nucleotide; D013577:Syndrome; D013939:Thymidine Phosphorylase / Q000235:genetics; D024182:Uniparental Disomy / Q000175:diagnosis*; D055815:Young Adult
D004272:DNA, Mitochondrial; C543750:TYMP protein, human; D013939:Thymidine Phosphorylase