Title: Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach
Authors: Zimoń, Magdalena ×
Battaloğlu, Esra
Parman, Yesim
Erdem, Sevim
Baets, Jonathan
De Vriendt, Els
Atkinson, Derek
Almeida-Souza, Leonardo
Deconinck, Tine
Ozes, Burcak
Goossens, Dirk
Cirak, Sebahattin
Van Damme, Philip
Shboul, Mohammad
Voit, Thomas
Van Maldergem, Lionel
Dan, Bernard
El-Khateeb, Mohammed S
Guergueltcheva, Velina
Lopez-Laso, Eduardo
Goemans, Nathalie
Masri, Amira
Züchner, Stephan
Timmerman, Vincent
Topaloğlu, Haluk
De Jonghe, Peter
Jordanova, Albena #
Issue Date: Jan-2015
Publisher: Oxford University Press
Series Title: Neurogenetics vol:16 issue:1 pages:33-42
Abstract: 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.
ISSN: 1364-6745
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory for Neurobiology (Vesalius Research Center)
Division of Geography & Tourism
Organ Systems (+)
× corresponding author
# (joint) last author

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