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

Ganka V. Douglas, Joanna Wiszniewska, Mark H. Lipson, David R. Witt, Taryn McDowell, Mara Sifry-Platt, Michio Hirano, William J. Craigen, Lee Jun C Wong

Research output: Contribution to journalArticle

12 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)834-839
Number of pages6
JournalJournal of Human Genetics
Volume56
Issue number12
DOIs
StatePublished - Dec 21 2011
Externally publishedYes

Fingerprint

Uniparental Disomy
Mitochondrial DNA
Single Nucleotide Polymorphism
Comparative Genomic Hybridization
Genes
Chromosomes, Human, Pair 22
Mutation
Chromosomes, Human, Pair 2
Genetic Counseling
Point Mutation
Fathers
Sequence Analysis
Molecular Biology
Parents
Mothers

Keywords

  • apparent homozygosity
  • autosomal recessive
  • mitochondrial DNA depletion syndrome
  • SNP array
  • uniparental isodisomy

ASJC Scopus subject areas

  • Genetics(clinical)
  • Genetics

Cite this

Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis. / Douglas, Ganka V.; Wiszniewska, Joanna; Lipson, Mark H.; Witt, David R.; McDowell, Taryn; Sifry-Platt, Mara; Hirano, Michio; Craigen, William J.; Wong, Lee Jun C.

In: Journal of Human Genetics, Vol. 56, No. 12, 21.12.2011, p. 834-839.

Research output: Contribution to journalArticle

Douglas, GV, Wiszniewska, J, Lipson, MH, Witt, DR, McDowell, T, Sifry-Platt, M, Hirano, M, Craigen, WJ & Wong, LJC 2011, 'Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis', Journal of Human Genetics, vol. 56, no. 12, pp. 834-839. https://doi.org/10.1038/jhg.2011.112
Douglas, Ganka V. ; Wiszniewska, Joanna ; Lipson, Mark H. ; Witt, David R. ; McDowell, Taryn ; Sifry-Platt, Mara ; Hirano, Michio ; Craigen, William J. ; Wong, Lee Jun C. / Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis. In: Journal of Human Genetics. 2011 ; Vol. 56, No. 12. pp. 834-839.
@article{c9a381290e1842c0a77131e05d8f9119,
title = "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.",
keywords = "apparent homozygosity, autosomal recessive, mitochondrial DNA depletion syndrome, SNP array, uniparental isodisomy",
author = "Douglas, {Ganka V.} and Joanna Wiszniewska and Lipson, {Mark H.} and Witt, {David R.} and Taryn McDowell and Mara Sifry-Platt and Michio Hirano and Craigen, {William J.} and Wong, {Lee Jun C}",
year = "2011",
month = "12",
day = "21",
doi = "10.1038/jhg.2011.112",
language = "English (US)",
volume = "56",
pages = "834--839",
journal = "Journal of Human Genetics",
issn = "1434-5161",
publisher = "Nature Publishing Group",
number = "12",

}

TY - JOUR

T1 - Detection of uniparental isodisomy in autosomal recessive mitochondrial DNA depletion syndrome by high-density SNP array analysis

AU - Douglas, Ganka V.

AU - Wiszniewska, Joanna

AU - Lipson, Mark H.

AU - Witt, David R.

AU - McDowell, Taryn

AU - Sifry-Platt, Mara

AU - Hirano, Michio

AU - Craigen, William J.

AU - Wong, Lee Jun C

PY - 2011/12/21

Y1 - 2011/12/21

N2 - 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.

AB - 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.

KW - apparent homozygosity

KW - autosomal recessive

KW - mitochondrial DNA depletion syndrome

KW - SNP array

KW - uniparental isodisomy

UR - http://www.scopus.com/inward/record.url?scp=84255188649&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84255188649&partnerID=8YFLogxK

U2 - 10.1038/jhg.2011.112

DO - 10.1038/jhg.2011.112

M3 - Article

C2 - 22011815

AN - SCOPUS:84255188649

VL - 56

SP - 834

EP - 839

JO - Journal of Human Genetics

JF - Journal of Human Genetics

SN - 1434-5161

IS - 12

ER -