title: De novo INF2 mutations expand the genetic spectrum of hereditary neuropathy with glomerulopathy.
abstract: OBJECTIVE
  Identification of mutations in the inverted formin-2 (INF2) gene in patients with Charcot-Marie-Tooth (CMT) disease combined with focal segmental glomerulosclerosis (FSGS) in order to expand the genetic and phenotypic spectrum.
  
  
  METHODS
  We sequenced INF2 in 5 patients with CMT disease and FSGS. Mutations were subsequently screened in family members of the index patient and 264 control individuals.
  
  
  RESULTS
  In 3 patients, we detected 2 novel de novo INF2 mutations (p.Leu77Arg and p.Leu69_Ser72del) and a third, most likely de novo mutation (p.Gly114Asp). One of our patients displayed intellectual disability, a phenotypic characteristic not previously associated with INF2. The same patient also showed a more pronounced sensorineural hearing loss than described before.
  
  
  CONCLUSIONS
  In exon 2 of INF2, we identified 3 novel mutations that likely affect the protein structure and function. Our findings expand the genetic spectrum of INF2-associated disorders and broaden the associated phenotype with the co-occurrence of intellectual disability and more severe hearing loss than previously reported. De novo INF2 mutations may be more common in patients with CMT disease and FSGS in comparison to FSGS alone. Furthermore, renal dysfunction is more severe and starts earlier in life when associated with CMT disease. Our study confirms that INF2 mutations are a major cause of disease in patients with CMT disease and early signs of nephropathy. Diagnostic screening of INF2 is strongly recommended in isolated patients presenting with CMT disease and FSGS.
authors.affiliation: From the Neurogenetics Group, VIB-Department of Molecular Genetics (I.M., T.D., P.D.J., J.B.), and Laboratory of Neurogenetics, Institute Born-Bunge (I.M., T.D., P.D.J., J.B.), University of Antwerp, Antwerpen, Belgium; University of Athens (A.D.); Attiko University Hospital (A.D.), Athens, Greece; Institute of Myology (T.V.), Paris, France; Department of Pediatric Neurology (U.S.), University of Essen, Essen, Germany; Centre for Human Genetics (K.D.), Department of Nephrology and Renal Transplantation (B.M.), and Pathology (E.L.), University Hospitals Leuven, Leuven, Belgium; Department of Imaging and Pathology (E.L.), KU Leuven, Leuven, Belgium; and Department of Neurology (P.D.J., J.B.), Antwerp University Hospital, Antwerpen, Belgium.
authors.forename: Inès
authors.initials: I
authors.lastname: Mademan
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Argirios
authors.initials: A
authors.lastname: Dinopoulos
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.forename: Ulrike
authors.initials: U
authors.lastname: Schara
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.forename: Björn
authors.initials: B
authors.lastname: Meijers
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lerut
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
authors.forename: Jonathan
authors.initials: J
authors.lastname: Baets
mesh_terms: D000293:Adolescent; D000328:Adult; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics*; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D000080865:Formins; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000235:genetics*; D006801:Humans; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics*; D008958:Models, Molecular; D009154:Mutation / Q000235:genetics*; D055815:Young Adult
chemical_list: D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins