Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis

Abstract

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.

Thymidine Phosphorylase Participates in Platelet Signaling and Promotes Thrombosis

“…Patients with this disorder generally die in early adulthood, although at this point no bleeding or thrombotic diathesis has been described. Heterozygous carriers have no discernible phenotype 52 . Indeed, no clinical symptoms of MNGIE were present in the Tymp −/− mice 15 .…”

Maternal uniparental disomy of chromosome 2 in a patient with a DGUOK mutation associated with hepatocerebral mitochondrial DNA depletion syndrome

“…The phenotype of our patient was clearly only the consequence of the homozygous DGUOK mutation. Recently, a paternal uniparental disomy of chromosome 2 was also identified in a DGUOK patient [25]. Since there were no other severe associated phenotype in all patients with complete UPD2, all these reports confirm that UPD2 is clinically silent and that imprinted genes are not located at chromosome 2.…”

Whole exome sequencing in a patient with uniparental disomy of chromosome 2 and a complex phenotype

“…Finally, UPD can lead to homozygosity of rare recessive mutations on the involved chromosome (31). Many cases of UPD2 resulting in the unmasking of rare recessive mutations are reported in the literature, including cases of Crigler-Najjar syndrome, Donnai-Barrow syndrome, severe congenital hypothyroidism, Harlequin ichthyosis, infantile-onset ascending spastic paralysis, long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency, and mitochondrial DNA depletion syndrome (13, 16, 18, 20, 21, 24). None of these subjects resemble the phenotype found in our proband, or any of its features, with the exception of one individual with retinal dystrophy believed to be caused by a recessive mutation in MERTK (27).…”