Autosomal recessive axonal polyneuropathy in a sibling pair due to a novel homozygous mutation in IGHMBP2.

Charcot-Marie-Tooth disease is a group of genetically heterogeneous disorders characterized by a sensorimotor polyneuropathy with subsequent muscle atrophy, areflexia, and sensory loss. More than 60 genes have been linked to Charcot-Marie-Tooth phenotypes, including IGHMBP2. Until recently, mutations in IGHMBP2 were exclusively associated with spinal muscular atrophy with respiratory distress (SMARD1). We present a sibling pair with a novel homozygous truncating mutation in IGHMBP2. The patients presented with childhood-onset distal weakness, wasting in the upper and lower limbs, areflexia and decreased sensation, but no respiratory involvement. Exome sequencing was performed and a homozygous variant was identified (c.2601_2604del; p.Lys868Profs*109). Sanger sequencing confirmed the presence of this variant in a homozygous state in the two affected siblings, while both parents were heterozygous. Further analyses showed decreased mRNA and IGHMBP2 protein in a lymphoblast cell line derived from one of the siblings. We demonstrate the utility of next-generation sequencing in reaching a molecular diagnosis for a heterogeneous condition such as Charcot-Marie-Tooth. Taken together, our data and that from the literature suggest that the spectrum of clinical presentations associated with mutations in IGHMBP2 may be secondary, at least in part, to the amount of residual protein.