Abstract
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited neuropathies. The purpose of this study is to identify the clinical and genetic diversity of peripheral myelin protein 22 (PMP22) in Chinese patients with CMT disease and evaluate their correlations with the clinical manifestations. Using the multiplex ligation-dependent probe amplification (MLPA) technique and Sanger sequencing of PMP22 in a cohort of 465 Chinese families between 2007 and 2019, we identified 137 pedigrees with PMP22 duplications (29.5%), 26 pedigrees with PMP22 deletions (5.6%), and 10 pedigrees with point mutations (2.2%). By comparing our data with the results from other CMT centers in China, we estimate that the frequency of PMP22 mutation in mainland China is ~23.3% (261/1120). We confirmed de novo mutations in 40% (4/10) of PMP22 point mutations. We have also identified two severely affected patients who are compound heterozygotes for recessive PMP22 mutations (novel mutation c.320-1 G>A and R157W mutation) and a 1.5 Mb deletion in 17p11.2-p12, suggesting that c.320-1 G>A might be another recessive allele contributing to DSS in addition to the T118M and R157W mutations. A de novo mutation of S79P in PMP22 was also identified concomitantly with the R94W mutation in mitofusin2 (MFN2). Our study highlights the phenotypic variability associated with PMP22 mutations in mainland China. The results provide valuable insights into the current strategy of genetic testing for CMT disease. NGS technology has increased the potential for efficient detection of variants of unknown significance (VUS) and concurrent causative genes. Greater cooperation between neurologists and molecular biologists is needed in future investigations.
Highlights
Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy and is characterized by progressive distal muscle weakness and atrophy, distal sensory loss and diminished deep tendon reflex [1, 2]
CMT1, 137 families were diagnosed with CMT2, 52 families were diagnosed with intermediate CMT disease and 30 families were diagnosed with hereditary neuropathy with liability to pressure palsies (HNPP)
Twenty-six index patients with peripheral myelin protein 22 (PMP22) deletions showed manifestations compatible with HNPP, and 10 index patients with PMP22 missense mutations and small deletions showed phenotypes ranging from CMT1E (2 index patients) to HNPP (2 index patients) and Dejerine-Sottas neuropathies (DSS) (6 index patients)
Summary
Charcot-Marie-Tooth (CMT) disease is the most common hereditary peripheral neuropathy and is characterized by progressive distal muscle weakness and atrophy, distal sensory loss and diminished deep tendon reflex [1, 2]. The most common cause of CMT disease is a large 1.5 Mb duplication of the 17p11.2 region that contains the gene for peripheral myelin protein 22 (PMP22), accounting for 70% of CMT1 and 50% of all CMT cases [2, 3]. The deletion of this region and point mutations and small deletions in the PMP22 gene are less common and may cause hereditary neuropathy with liability to pressure palsies (HNPP), Dejerine-Sottas neuropathies (DSS) and CMT1E [4, 5]. [2] Patients with a 17p11.2 duplication and micro mutations in PMP22 present with varying levels of severity of the disease. We summarize the results obtained from a large cohort of Chinese patients and compare our results with data from other major CMT centers in the northern and southern parts of China. We aimed to investigate the clinical and electrophysiological diversity of variations, including the specific genotypes/phenotypes, in mainland China and provide new insights into the phenotypic spectrum of specific genetic subgroups
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