Genetic diagnosis of two dopa-responsive dystonia families by exome sequencing

PLoS One. 2014 Sep 2;9(9):e106388. doi: 10.1371/journal.pone.0106388. eCollection 2014.

Abstract

Dopa-responsive dystonia, a rare disorder typically presenting in early childhood with lower limb dystonia and gait abnormality, responds well to levodopa. However, it is often misdiagnosed with the wide spectrum of phenotypes. By exome sequencing, we make a rapid genetic diagnosis for two atypical dopa-responsive dystonia pedigrees. One pedigree, presented with prominent parkinsonism, was misdiagnosed as Parkinson's disease until a known mutation in GCH1 (GTP cyclohydrolase 1) gene (NM_000161.2: c.631_632delAT, p.Met211ValfsX38) was found. The other pedigree was detected with a new compound heterozygous mutation in TH (tyrosine hydroxylase) gene [(NM_000360.3: c.911C>T, p.Ala304Val) and (NM_000360.3: c.1358G>A, p.Arg453His)], whose proband, a pregnant woman, required a rapid and less-biased genetic diagnosis. In conclusion, we demonstrated that exome sequencing could provide a precise and rapid genetic testing in the diagnosis of Mendelian diseases, especially for diseases with wide phenotypes.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Amino Acid Sequence
  • Base Sequence
  • Cell Extracts
  • Child, Preschool
  • Dystonic Disorders / diagnosis*
  • Dystonic Disorders / genetics*
  • Exome / genetics*
  • Female
  • GTP Cyclohydrolase / chemistry
  • GTP Cyclohydrolase / genetics
  • Genetic Testing*
  • Humans
  • Male
  • Middle Aged
  • Molecular Sequence Data
  • Mutant Proteins / metabolism
  • Mutation / genetics
  • Sequence Analysis, DNA / methods*
  • Transfection
  • Tyrosine 3-Monooxygenase / metabolism
  • Young Adult

Substances

  • Cell Extracts
  • Mutant Proteins
  • Tyrosine 3-Monooxygenase
  • GTP Cyclohydrolase

Supplementary concepts

  • Dystonia, Dopa-responsive

Grants and funding

This study was supported by the Major State Basic Research Development Program of China (973 Program) (grant number 2011CB510000 to Bei-sha Tang), the State Key Program of National Natural Science Foundation of China (grant number 81130021 to Bei-sha Tang), and the public industry research and special projects from National Health and Family Planning Commission of China (grant number 201302001 to Bei-sha Tang), and Graduate Innovation Project in Hunan province (to Zhan-fang Sun). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.