A de novo EGR2 variant, c.1232A\u2009>\u2009G p.Asp411Gly, causes severe early-onset Charcot-Marie-Tooth Neuropathy Type 3 (Dejerine-Sottas Neuropathy)

Bianca R Grosz,Anthony Antonellis,Natasha B Golovchenko,Marina L Kennerson,Melina Ellis,Kishore Kumar,Garth A Nicholson

doi:10.1038/s41598-019-55875-4

Abstract

EGR2 (early growth response 2) is a crucial transcription factor for the myelination of the peripheral nervous system. Mutations in EGR2 are reported to cause a heterogenous spectrum of peripheral neuropathy with wide variation in both severity and age of onset, including demyelinating and axonal forms of Charcot-Marie Tooth (CMT) neuropathy, Dejerine-Sottas neuropathy (DSN/CMT3), and congenital hypomyelinating neuropathy (CHN/CMT4E). Here we report a sporadic de novo EGR2 variant, c.1232A > G (NM_000399.5), causing a missense p.Asp411Gly substitution and discovered through whole-exome sequencing (WES) of the proband. The resultant phenotype is severe demyelinating DSN with onset at two years of age, confirmed through nerve biopsy and electrophysiological examination. In silico analyses showed that the Asp411 residue is evolutionarily conserved, and the p.Asp411Gly variant was predicted to be deleterious by multiple in silico analyses. A luciferase-based reporter assay confirmed the reduced ability of p.Asp411Gly EGR2 to activate a PMP22 (peripheral myelin protein 22) enhancer element compared to wild-type EGR2. This study adds further support to the heterogeneity of EGR2-related peripheral neuropathies and provides strong functional evidence for the pathogenicity of the p.Asp411Gly EGR2 variant.

Highlights

Charcot-Marie-Tooth (CMT) neuropathy is group of degenerative motor and sensory peripheral neuropathies which are clinically and genetically heterogenous
The spectrum of peripheral neuropathy associated with disease-causing EGR2 variants ranges from severe early onset DSN and CHN, to later onset demyelinating CMT1 and axonal CMT2
Using whole-exome sequencing (WES) and functional testing we have determined that a de novo missense EGR2 variant, c.1232A > G p.Asp411Gly, causes a severe and early onset DSN phenotype by reducing the capacity for EGR2 to function as a transcription factor

Summary

Introduction

Charcot-Marie-Tooth (CMT) neuropathy is group of degenerative motor and sensory peripheral neuropathies which are clinically and genetically heterogenous. Pathogenic variants in the EGR2 gene (early growth response 2) cause a broad spectrum of peripheral neuropathy phenotypes. We report a sporadic de novo EGR2 variant in the third zinc-finger domain, c.1232A > G p.Asp411Gly, discovered through WES candidate gene screening. This variant manifested as a severe DSN phenotype with early onset at two years of age

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