title: Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach.
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.
authors.affiliation: Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Universiteitsplein 1, 2610, Antwerp, Belgium.
authors.forename: Magdalena
authors.initials: M
authors.lastname: Zimoń
authors.forename: Esra
authors.initials: E
authors.lastname: Battaloğlu
authors.forename: Yesim
authors.initials: Y
authors.lastname: Parman
authors.forename: Sevim
authors.initials: S
authors.lastname: Erdem
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
authors.forename: Els
authors.initials: E
authors.lastname: De Vriendt
authors.forename: Derek
authors.initials: D
authors.lastname: Atkinson
authors.forename: Leonardo
authors.initials: L
authors.lastname: Almeida-Souza
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Burcak
authors.initials: B
authors.lastname: Ozes
authors.forename: Dirk
authors.initials: D
authors.lastname: Goossens
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.forename: Philip
authors.initials: P
authors.lastname: Van Damme
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shboul
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Lionel
authors.initials: L
authors.lastname: Van Maldergem
authors.forename: Bernard
authors.initials: B
authors.lastname: Dan
authors.forename: Mohammed S
authors.initials: MS
authors.lastname: El-Khateeb
authors.forename: Velina
authors.initials: V
authors.lastname: Guergueltcheva
authors.forename: Eduardo
authors.initials: E
authors.lastname: Lopez-Laso
authors.forename: Nathalie
authors.initials: N
authors.lastname: Goemans
authors.forename: Amira
authors.initials: A
authors.lastname: Masri
authors.forename: Stephan
authors.initials: S
authors.lastname: Züchner
authors.forename: Vincent
authors.initials: V
authors.lastname: Timmerman
authors.forename: Haluk
authors.initials: H
authors.lastname: Topaloğlu
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
mesh_terms: D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis* / Q000235:genetics*; D002874:Chromosome Mapping; D004252:DNA Mutational Analysis; D005260:Female; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000235:genetics; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics
chemical_list: C118663:GDAP protein; C063306:HINT1 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D009419:Nerve Tissue Proteins; D011506:Proteins; C488620:SH3TC2 protein, human