Genetic spectrum and clinical profiles in a southeast Chinese cohort of Charcot‐Marie‐Tooth disease

Abstract

Charcot‐Marie‐Tooth (CMT) disease is a heterogeneous group of inherited sensorimotor neuropathies. To clarify the genetic spectrum and clinical profiles in Chinese CMT patients, we enrolled 150 unrelated CMT patients from southeast China. We performed multiplex ligation‐dependent probe amplification (MLPA) testing in all patients and next‐generation sequencing (NGS) among those patients without PMP22 rearrangements. We identified PMP22 duplications in 40 patients and deletions in 12 patients. In addition, we found 19 novel variants and 36 known mutations in 57 patients. Among these 55 variants, 45 pathogenic or likely pathogenic variants were identified in 48 cases, and 10 variants with uncertain significance were identified in 9 cases. Therefore, we obtained a genetic diagnosis in 63.8% (88/138) of CMT patients and 66.7% (100/150) of all included patients. PMP22, GJB1, and MFN2 are the most common causative genes in CMT1 (demyelinated form), intermediate CMT, and CMT2 (axonal form), respectively. In this study, we identified a higher proportion of intermediate CMT, a relatively high frequency of NDRG1 mutations and clinical features of later onset age in CMT1A patients. Our results broaden the genetic and clinical spectrum of CMT patients, which can help optimize the genetic and clinical diagnosis.

Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot–Marie–Tooth disease

“…Besides the three families carrying variants in GDAP1 in this study, we have previously reported three GDAP1 variants (p.W31*, p.Q38*, p.V215I) in two patients 22 . The locations of seven variants from our studies and 10 variants from other Chinese studies in the structure of GDAP1 protein are shown in Figure 1C.…”

“…Herein, we focus on the three novel variants (p.L26R, p.S169fs, c.694 + 1G>A) and one known variant (p.R120W) in GDAP1 . Taking three variants previously reported in two patients into consideration, 22 we can summarize a frequency distribution of 2.78% (5/180) in GDAP1 . Previous studies in the Chinese population showed a similar frequency 4,9 .…”

Identification and functional characterization of novel GDAP1 variants in Chinese patients with Charcot-Marie-Tooth disease

“…Besides the three families carrying variants in GDAP1 in this study, we have previously reported three GDAP1 variants (p.W31X, p.Q38X, p.V215I) in 2 patients (Chen et al, 2019). The location of 7 variants from our studies and 10 variants from other Chinese studies in the structure of GDAP1 protein are shown in Fig.…”

“…Herein, we focus on the three novel variants (p.L26R, p.S169fs, c.694+1G>A) and one known variant (p.R120W) inGDAP1 . Taking 3 variants previously reported in 2 patients into consideration (Chen et al, 2019), we can summarize a frequency distribution of 2.78% (5/180) in GDAP1 . Previous studies in the Chinese population showed the similar frequency (Fu et al, 2017;Pakhrin et al, 2018).…”

Genetic Spectrum and Clinical Features in a Cohort of Chinese Patients with Autosomal Recessive Cerebellar Ataxias

“…Despite the discovery of many disease-causing genes in recent years, the genetic cause of ARCAs remains elusive in more than 50% of affected individuals [8,9]. The advent of whole-exome sequencing (WES) technology not only has enabled the e cient diagnosis with single-nucleotide variants (SNVs) and small indels [10], but also the new WES-based method, such as Exome Depth, has successfully detected structural variation (SV) like copy number variations (CNVs) in many hereditary diseases [11]. Moreover, owing to the low incidence, there are few studies reported the rare genetic or clinical characteristic of ARCA patients in the Chinese population.…”