Whole genome sequencing reveals novel IGHMBP2 variant leading to unique cryptic splice‐site and Charcot‐Marie‐Tooth phenotype with early onset symptoms

BACKGROUND: Rare variants (RV) in immunoglobulin mu‐binding protein 2 (IGHMBP2) [OMIM 600502] can cause an autosomal recessive type of Charcot‐Marie‐Tooth (CMT) disease [OMIM 616155], an inherited peripheral neuropathy. Over 40 different genes are associated with CMT, with different possible inheritance patterns. METHODS AND RESULTS: An 11‐year‐old female with motor delays was found to have distal atrophy, weakness, and areflexia without bulbar or sensory findings. Her clinical evaluation was unrevealing. Whole exome sequencing (WES) revealed a maternally inherited IGHMBP2 RV (c.1730T>C) predicted to be pathogenic, but no variant on the other allele was identified. Deletion and duplication analysis was negative. She was referred to the Undiagnosed Disease Network (UDN) for further evaluation. Whole genome sequencing (WGS) confirmed the previously identified IGHMBP2 RV and identified a paternally inherited non‐coding IGHMBP2 RV. This was predicted to activate a cryptic splice site perturbing IGHMBP2 splicing. Reverse transcriptase polymerase chain reaction (RT‐PCR) analysis was consistent with activation of the cryptic splice site. The abnormal transcript was shown to undergo nonsense‐mediated decay (NMD), resulting in halpoinsufficiency. CONCLUSION: This case demonstrates the deficiencies of WES and traditional molecular analyses and highlights the advantages of utilization of WGS and functional studies.