Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease

Mark B. Consugar, Sarah A. Anderson, Sandro Rossetti, V. Shane Pankratz, Christopher J. Ward, Roser Torra, Eliecer Coto, Monif El-Youssef, Sibel Kantarci, Boris Utsch, Friedhelm Hildebrandt, William E. Sweeney, Ellis D. Avner, Vicente Torres, Julie M Cunningham, Peter C Harris

Research output: Contribution to journalArticle

26 Citations (Scopus)

Abstract

Background: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1, covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping. Methods: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1. Results: Examples in which haplotype analysis, used in combination with mutation screening, improved the utility of molecular diagnostics, especially in families in which just a single PKHD1 mutation has been identified, are illustrated. The new markers also allow screening for larger DNA deletions, detecting unknown consanguinity and exploring the disease mechanism. Analysis of 8 recurring mutations has shown likely common haplotypes for each, and the divergence from the ancestral haplotype, by recombination, can be used to trace the history of the mutation. The common mutation, T36M, was found to have a single European origin, about 1,225 years ago. Conclusion: Improved haplotype analysis of ARPKD complements mutation-based diagnostics and helps trace the history of common PKHD1 mutations.

Original languageEnglish (US)
Pages (from-to)77-87
Number of pages11
JournalAmerican Journal of Kidney Diseases
Volume45
Issue number1
DOIs
StatePublished - Jan 2005

Fingerprint

Autosomal Recessive Polycystic Kidney
Molecular Pathology
Haplotypes
Mutation
History
Consanguinity
Multiplex Polymerase Chain Reaction
DNA
Microsatellite Repeats
Genetic Recombination
Exons
Fluorescence

Keywords

  • ancestral mutations
  • Autosomal recessive polycystic kidney disease (ARPKD)
  • haplotype analysis
  • molecular diagnostics
  • PKHD1
  • prenatal diagnosis

ASJC Scopus subject areas

  • Nephrology

Cite this

Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease. / Consugar, Mark B.; Anderson, Sarah A.; Rossetti, Sandro; Pankratz, V. Shane; Ward, Christopher J.; Torra, Roser; Coto, Eliecer; El-Youssef, Monif; Kantarci, Sibel; Utsch, Boris; Hildebrandt, Friedhelm; Sweeney, William E.; Avner, Ellis D.; Torres, Vicente; Cunningham, Julie M; Harris, Peter C.

In: American Journal of Kidney Diseases, Vol. 45, No. 1, 01.2005, p. 77-87.

Research output: Contribution to journalArticle

Consugar, MB, Anderson, SA, Rossetti, S, Pankratz, VS, Ward, CJ, Torra, R, Coto, E, El-Youssef, M, Kantarci, S, Utsch, B, Hildebrandt, F, Sweeney, WE, Avner, ED, Torres, V, Cunningham, JM & Harris, PC 2005, 'Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease', American Journal of Kidney Diseases, vol. 45, no. 1, pp. 77-87. https://doi.org/10.1053/j.ajkd.2004.09.009
Consugar, Mark B. ; Anderson, Sarah A. ; Rossetti, Sandro ; Pankratz, V. Shane ; Ward, Christopher J. ; Torra, Roser ; Coto, Eliecer ; El-Youssef, Monif ; Kantarci, Sibel ; Utsch, Boris ; Hildebrandt, Friedhelm ; Sweeney, William E. ; Avner, Ellis D. ; Torres, Vicente ; Cunningham, Julie M ; Harris, Peter C. / Haplotype analysis improves molecular diagnostics of autosomal recessive polycystic kidney disease. In: American Journal of Kidney Diseases. 2005 ; Vol. 45, No. 1. pp. 77-87.
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abstract = "Background: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1, covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping. Methods: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1. Results: Examples in which haplotype analysis, used in combination with mutation screening, improved the utility of molecular diagnostics, especially in families in which just a single PKHD1 mutation has been identified, are illustrated. The new markers also allow screening for larger DNA deletions, detecting unknown consanguinity and exploring the disease mechanism. Analysis of 8 recurring mutations has shown likely common haplotypes for each, and the divergence from the ancestral haplotype, by recombination, can be used to trace the history of the mutation. The common mutation, T36M, was found to have a single European origin, about 1,225 years ago. Conclusion: Improved haplotype analysis of ARPKD complements mutation-based diagnostics and helps trace the history of common PKHD1 mutations.",
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AU - Anderson, Sarah A.

AU - Rossetti, Sandro

AU - Pankratz, V. Shane

AU - Ward, Christopher J.

AU - Torra, Roser

AU - Coto, Eliecer

AU - El-Youssef, Monif

AU - Kantarci, Sibel

AU - Utsch, Boris

AU - Hildebrandt, Friedhelm

AU - Sweeney, William E.

AU - Avner, Ellis D.

AU - Torres, Vicente

AU - Cunningham, Julie M

AU - Harris, Peter C

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N2 - Background: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1, covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping. Methods: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1. Results: Examples in which haplotype analysis, used in combination with mutation screening, improved the utility of molecular diagnostics, especially in families in which just a single PKHD1 mutation has been identified, are illustrated. The new markers also allow screening for larger DNA deletions, detecting unknown consanguinity and exploring the disease mechanism. Analysis of 8 recurring mutations has shown likely common haplotypes for each, and the divergence from the ancestral haplotype, by recombination, can be used to trace the history of the mutation. The common mutation, T36M, was found to have a single European origin, about 1,225 years ago. Conclusion: Improved haplotype analysis of ARPKD complements mutation-based diagnostics and helps trace the history of common PKHD1 mutations.

AB - Background: Autosomal recessive polycystic kidney disease (ARPKD) is characterized by wide phenotypic variability, ranging from in utero detection with enlarged, echogenic kidneys to an adult presentation with congenital hepatic fibrosis. The ARPKD gene, PKHD1, covers about 470 kb of DNA (67 exons), and mutation studies have found marked allelic heterogeneity with a high level of novel missense changes and neutral polymorphisms. To improve the prospects for molecular diagnostics and to study the origin of some relatively common mutations, the authors have developed a strategy for improved ARPKD haplotyping. Methods: A protocol of multiplex PCR and fluorescence genotyping in a single capillary has been developed to assay 7 highly informative simple sequence repeat (SSR) markers that are intragenic or closely flanking PKHD1. Results: Examples in which haplotype analysis, used in combination with mutation screening, improved the utility of molecular diagnostics, especially in families in which just a single PKHD1 mutation has been identified, are illustrated. The new markers also allow screening for larger DNA deletions, detecting unknown consanguinity and exploring the disease mechanism. Analysis of 8 recurring mutations has shown likely common haplotypes for each, and the divergence from the ancestral haplotype, by recombination, can be used to trace the history of the mutation. The common mutation, T36M, was found to have a single European origin, about 1,225 years ago. Conclusion: Improved haplotype analysis of ARPKD complements mutation-based diagnostics and helps trace the history of common PKHD1 mutations.

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