title: A novel mutation in FGD4/FRABIN causes Charcot Marie Tooth disease type 4H in patients from a consanguineous Tunisian family.
abstract: Charcot-Marie-Tooth (CMT) disease constitutes a clinically and genetically heterogeneous group of hereditary neuropathies characterized by progressive muscular and sensory loss in the distal extremities with chronic distal weakness, deformation of the feet, and loss of deep tendon reflexes. CMT4H is an autosomal recessive demyelinating subtype of CMT, due to mutations in FGD4/FRABIN, for which nine mutations are described to date. In this study, we describe three patients from a consanguineous Tunisian family, presenting with severe, early onset, slowly progressive, autosomal recessive demyelinating CMT, complicated by mild to severe kyphoscoliosis, consistent with CMT4H. In these patients, we report the identification of a novel homozygous frameshift mutation in FGD4: c.514_515insG; p.Ala172Glyfs*27. Our study reports the first mutation identified in FGD4 in Tunisian patients affected with CMT. It further confirms the important clinical heterogeneity observed in patients with mutations in FGD4 and the lack of phenotype/genotype correlations in CMT4H. Our results suggest that FGD4 should be screened in other early-onset CMT subtypes, regardless of the severity of the phenotype, and particularly in patients of consanguineous descent. In Tunisians, as in other populations with high consanguinity rates, screening of genes responsible for rare autosomal recessive CMT subtypes should be prioritized.
authors.affiliation: Inserm, UMR_S 910, "Génétique Médicale et Génomique Fonctionnelle", Faculté de Médecine de la Timone, 13385, Marseille, France; Aix-Marseille University, UMR_S 910, "Génétique Médicale et Génomique Fonctionnelle", Faculté de Médecine de la Timone, 13385, Marseille, France; Laboratoire d'Histologie, de Cytologie et de Génétique, Université de Monastir, Faculté de Médecine, Monastir, Tunisia.
authors.forename: Chokri
authors.initials: C
authors.lastname: Boubaker
authors.forename: Inès
authors.initials: I
authors.lastname: Hsairi-Guidara
authors.forename: Christel
authors.initials: C
authors.lastname: Castro
authors.forename: Ines
authors.initials: I
authors.lastname: Ayadi
authors.forename: Amandine
authors.initials: A
authors.lastname: Boyer
authors.forename: Emna
authors.initials: E
authors.lastname: Kerkeni
authors.forename: Joël
authors.initials: J
authors.lastname: Courageot
authors.forename: Imen
authors.initials: I
authors.lastname: Abid
authors.forename: Rafaëlle
authors.initials: R
authors.lastname: Bernard
authors.forename: Nathalie
authors.initials: N
authors.lastname: Bonello-Palot
authors.forename: Fatma
authors.initials: F
authors.lastname: Kamoun
authors.forename: Hassen Ben
authors.initials: HB
authors.lastname: Cheikh
authors.forename: Nicolas
authors.initials: N
authors.lastname: Lévy
authors.forename: Chahnez
authors.initials: C
authors.lastname: Triki
authors.forename: Valérie
authors.initials: V
authors.lastname: Delague
mesh_terms: D000293:Adolescent; D001706:Biopsy; D002607:Charcot-Marie-Tooth Disease / Q000175:diagnosis / Q000235:genetics*; D002648:Child; D003241:Consanguinity; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D009154:Mutation; D009413:Nerve Fibers, Myelinated / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D014416:Tunisia; D055815:Young Adult
chemical_list: C485164:FGD4 protein, human; D008840:Microfilament Proteins
keywords: Charcot‐Marie‐Tooth disease; FRABIN; disease gene; homozygous mutation; neuropathy; peripheral nerve