G.P.240: Next Generation Sequencing reveals IGHMBP2 variants as a cause for distal hereditary motor neuronopathy in two children

Abstract

IGHMBP2 variants are associated with autosomal recessive distal spinal muscular atrophy 1 and distal hereditary motor neuronopathy type VI (dHMN6). Here we present two patients with potentially pathogenic variants in IGHMBP2 gene. Case 1-A 16 year old male patient with a progressive distal weakness and deformity of both hands and feet which presented in childhood. He also had marked pain (possibly radicular in origin) mainly in toes and chest, which was severe enough to require opiates. His hands showed marked thenar and hypothenar loss of muscle bulk. Neurophysiological investigations revealed an active and partial chronic denervation. Initial genetic investigations did not reveal any abnormalities. His DNA was subsequently analysed by gene panel testing. Gene panel testing (simultaneous testing of 56 genes associated with the common and the rare causes of different types of inherited peripheral neuropathy) revealed a single heterozygous frameshift variant in exon 5 of the IGHMBP2 gene; c.661del, p. (Thr221Profs*12). No second variant was identified in this patient. It is likely to be pathogenic as it is expected to cause premature truncation of the mRNA, leading either to the production of a non-functional protein, or no protein product from that allele due to nonsense mediated decay. Case 2 -A 12 year old female presented with gait problems, clumsiness, and recurrent falls at the age of 5 years. Neurophysiological investigations revealed a demyelinating neuropathy. Her initial gene testing was negative. Her DNA was subsequently analysed by gene panel testing. Two heterozygous frameshift variants were detected in the IGHMBP2 gene; c.2356delG, p. (Ala786Profs*45) in exon 13, and c.2911_2912delAG, p. (Arg971Glufs*4) in exon 15. Parents of the proband were tested and each was found to be heterozygous for one IGHMBP2 variant, confirming that the two variants are in trans in their daughter. Further studies will be needed to establish pathogenicity. IGHMBP2 variants are associated with autosomal recessive distal spinal muscular atrophy 1 and distal hereditary motor neuronopathy type VI (dHMN6). Here we present two patients with potentially pathogenic variants in IGHMBP2 gene. Case 1-A 16 year old male patient with a progressive distal weakness and deformity of both hands and feet which presented in childhood. He also had marked pain (possibly radicular in origin) mainly in toes and chest, which was severe enough to require opiates. His hands showed marked thenar and hypothenar loss of muscle bulk. Neurophysiological investigations revealed an active and partial chronic denervation. Initial genetic investigations did not reveal any abnormalities. His DNA was subsequently analysed by gene panel testing. Gene panel testing (simultaneous testing of 56 genes associated with the common and the rare causes of different types of inherited peripheral neuropathy) revealed a single heterozygous frameshift variant in exon 5 of the IGHMBP2 gene; c.661del, p. (Thr221Profs*12). No second variant was identified in this patient. It is likely to be pathogenic as it is expected to cause premature truncation of the mRNA, leading either to the production of a non-functional protein, or no protein product from that allele due to nonsense mediated decay. Case 2 -A 12 year old female presented with gait problems, clumsiness, and recurrent falls at the age of 5 years. Neurophysiological investigations revealed a demyelinating neuropathy. Her initial gene testing was negative. Her DNA was subsequently analysed by gene panel testing. Two heterozygous frameshift variants were detected in the IGHMBP2 gene; c.2356delG, p. (Ala786Profs*45) in exon 13, and c.2911_2912delAG, p. (Arg971Glufs*4) in exon 15. Parents of the proband were tested and each was found to be heterozygous for one IGHMBP2 variant, confirming that the two variants are in trans in their daughter. Further studies will be needed to establish pathogenicity.