This study aimed to identify 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. INF2 was sequenced in 5 patients with CMT disease and FSGS. Mutations were subsequently screened in family members of the index patient and 264 control individuals. In 3 patients, 2 novel de novo INF2 mutations (p.Leu77Arg and p.Leu69_Ser72del) and a third, most likely de novo mutation (p.Gly114Asp) were detected. One of the patients displayed intellectual disability, a phenotypic characteristic not previously associated with INF2. The same patient also showed a more pronounced sensorineural hearing loss than previously described. In exon 2 of INF2, the authors identified 3 novel mutations that likely affect the protein structure and function. Their 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. This 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.
