TUBITAK Destekli Projelerden Çıkan Yayınlar Topluluğu
Published January 1, 2015 | Version v1
Journal article Open

Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach

Creators

  • 1. Bogazici Univ, Dept Mol Biol & Genet, Istanbul, Turkey
  • 2. Istanbul Univ, Istanbul Fac Med, Dept Neurol, Istanbul, Turkey
  • 3. Hacettepe Univ, Fac Med, Dept Neurol, TR-06100 Ankara, Turkey
  • 4. Univ Antwerp, VIB Dept Mol Genet, Appl Mol Genom Unit, B-2610 Antwerp, Belgium
  • 5. Childrens Natl Med Ctr, Med Genet Res Ctr, Washington, DC 20010 USA
  • 6. ASTAR, Inst Med Biol, Singapore, Singapore
  • 7. Univ Paris 06, Inst Myol, Unite Morphol Neuromusculaire, Paris, France
  • 8. Univ Franche Comte, Ctr Genet Humaine, F-25030 Besancon, France
  • 9. Univ Libre Bruxelles, Hop Univ Enfants Reine Fabiola, Dept Neurol, Brussels, Belgium
  • 10. Univ Jordan, Fac Med, Genet Lab, Amman, Jordan
  • 11. Med Univ Sofia, Dept Neurol, Sofia, Bulgaria
  • 12. Univ Hosp Reina Sofia, Cordoba, Spain

Description

Autosomal recessive forms of Charcot-Marie-Tooth disease (ARCMT) are rare but severe disorders of the peripheral nervous system. Their molecular basis is poorly understood due to the extensive genetic and clinical heterogeneity, posing considerable challenges for patients, physicians, and researchers. We report on the genetic findings from a systematic study of a large collection of 174 independent ARCMT families. Initial sequencing of the three most common ARCMT genes (ganglioside-induced differentiation protein 1-GDAP1, SH3 domain and tetratricopeptide repeats-containing protein 2-SH3TC2, histidine-triad nucleotide binding protein 1-HINT1) identified pathogenic mutations in 41 patients. Subsequently, 87 selected nuclear families underwent single nucleotide polymorphism (SNP) genotyping and homozygosity mapping, followed by targeted screening of known ARCMT genes. This strategy provided molecular diagnosis to 22 % of the families. Altogether, our unbiased genetic approach identified pathogenic mutations in ten ARCMT genes in a total of 41.3 % patients. Apart from a newly described founder mutation in GDAP1, the majority of variants constitute private molecular defects. Since the gene testing was independent of the clinical phenotype of the patients, we identified mutations in patients with unusual or additional clinical features, extending the phenotypic spectrum of the SH3TC2 gene. Our study provides an overview of the ARCMT genetic landscape and proposes guidelines for tackling the genetic heterogeneity of this group of hereditary neuropathies.

Files

bib-74d7f058-20ec-4e5d-8633-1f8dbba6fd03.txt

Files (442 Bytes)

Name Size Download all
md5:45dfc4c7283253492dde090c7cffcdda
442 Bytes Preview Download