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Case Reports
. 2019 Jun;7(6):e00676.
doi: 10.1002/mgg3.676. Epub 2019 Apr 25.

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

Thomas A Cassini  1   2 , Laura Duncan  1 , Lynette C Rives  1 , John H Newman  2 , John A Phillips  1 , Mary E Koziura  1 , Jennifer Brault  1 , Rizwan Hamid  1 , Joy Cogan  1 ; Undiagnosed Diseases Network
Collaborators, Affiliations
Case Reports

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

Thomas A Cassini et al. Mol Genet Genomic Med. 2019 Jun.

Abstract

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.

Keywords: IGHMBP2; Charcot-Marie-Tooth; Undiagnosed Disease Network; intron; splicing; whole exome sequencing.

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Conflict of interest statement

The authors have no disclosures or conflicts of interest.

Figures

Figure 1
Figure 1
Photographs of the patient demonstrating distal atrophy
Figure 2
Figure 2
IGHMBP2 (NM_0021180.2) cDNA sequencing in the presence and absence of puromycin, an inhibitor of nonsense ‐mediated decay (NMD). The top panel shows sequencing in the presence of puromycin demonstrating both a reference sequence of exon 9 and an intervening sequence (IVS) as a result of the c.1235 + 984 C>A variant. The bottom panel shows that in the absence of puromycin the IVS is absent, indicating it is subject to NMD
Figure 3
Figure 3
Diagram of splice site disruption of IGHMBP2 (NM_0021180.2). Genomic localization of the pseudoexon (solid black box) with the spliced‐in 182‐bp sequence in capital letters. The location of the mutated base is indicated (asterisk), the used intronic donor splice site (GT) is underlined. The additional 182 bp results in the insertion of a stop codon (outlined boxed) and premature termination of translation
See this image and copyright information in PMC

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