TY - JOUR
T1 - Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach
AU - Zimoń, Magdalena
AU - Battaloğlu, Esra
AU - Parman, Yesim
AU - Erdem, Sevim
AU - Baets, Jonathan
AU - De Vriendt, Els
AU - Atkinson, Derek
AU - Almeida-Souza, Leonardo
AU - Deconinck, Tine
AU - Ozes, Burcak
AU - Goossens, Dirk
AU - Cirak, Sebahattin
AU - Van Damme, Philip
AU - Shboul, Mohammad
AU - Voit, Thomas
AU - Van Maldergem, Lionel
AU - Dan, Bernard
AU - El-Khateeb, Mohammed S.
AU - Guergueltcheva, Velina
AU - Lopez-Laso, Eduardo
AU - Goemans, Nathalie
AU - Masri, Amira
AU - Züchner, Stephan
AU - Timmerman, Vincent
AU - Topaloğlu, Haluk
AU - De Jonghe, Peter
AU - Jordanova, Albena
N1 - Publisher Copyright:
© 2014, Springer-Verlag Berlin Heidelberg.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2014/1
Y1 - 2014/1
N2 - 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.
AB - 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.
KW - CMT
KW - Charcot-Marie-Tooth disease
KW - Homozygosity mapping
KW - Inbred populations
KW - Whole genome SNP genotyping
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U2 - 10.1007/s10048-014-0422-0
DO - 10.1007/s10048-014-0422-0
M3 - Article
C2 - 25231362
AN - SCOPUS:84920525366
VL - 16
SP - 33
EP - 42
JO - Neurogenetics
JF - Neurogenetics
SN - 1364-6745
IS - 1
ER -