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Mutations causing medullary cystic kidney disease type 1 lie in a large VNTR in MUC1 missed by massively parallel

Andrew Kirby1, Andreas Gnirke, David B Jaffe

  • 1Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA.

Nature Genetics
|February 12, 2013
PubMed

Insights

Identifying genetic causes of rare diseases like medullary cystic kidney disease type 1 (MCKD1) can be challenging. Massively parallel sequencing missed mutations in a difficult-to-sequence MUC1 gene region, highlighting limitations in genetic disorder discovery.

Area of Science:

  • Genetics
  • Molecular Biology
  • Medical Research

Background:

  • Genetic lesions for Mendelian disorders are often found using massively parallel sequencing (MPS).
  • However, some diseases remain challenging to diagnose with current sequencing technologies.
  • Medullary cystic kidney disease type 1 (MCKD1) was previously mapped to chromosome 1.

Purpose of the Study:

  • To identify the genetic cause of medullary cystic kidney disease type 1 (MCKD1).
  • To investigate the limitations of massively parallel sequencing in diagnosing certain genetic disorders.

Main Methods:

  • Case study of six families with MCKD1.
  • Utilized cloning, capillary sequencing, and de novo assembly.
  • Analyzed mutations within the MUC1 gene's variable-number tandem repeat (VNTR) region.

Main Results:

  • Identified mutations in the MUC1 gene in all six MCKD1 families.
  • Mutations involved the insertion of a single cytosine within a long, GC-rich VNTR sequence.
  • These specific VNTR sequences were under-represented in MPS data, leading to missed diagnoses.
  • Identical mutations arose independently in different families.

Conclusions:

  • The study highlights the challenges of using MPS for diagnosing Mendelian disorders with complex genetic mutations.
  • Difficult-to-sequence regions, such as long, GC-rich VNTRs in the MUC1 gene, can obscure causative mutations.
  • Alternative sequencing and assembly methods are crucial for identifying mutations in challenging genomic regions.

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