Phenotype-genotype correlation in X-linked Charcot-Marie-Tooth disease: A French cohort study

Abstract

Background and purpose: X-linked Charcot-Marie-Tooth disease type 1 (CMTX1) ranks as the second most prevalent hereditary neuropathy and, currently, has no definitive cure. Emerging preclinical trials offer hope for potential clinical studies in the near future. While it is widely accepted that experimental groups in these trials should be balanced for age and gender, there is a current shortfall in data regarding phenotype-genotype correlations. Our aim was to provide a more detailed understanding of these correlations to facilitate the formation of well-matched patient groups in upcoming clinical trials.

Methods: We conducted a retrospective evaluation of CMTX1 patients from 13 designated reference centers in France. Data on genetics, clinical features, and nerve conduction were systematically gathered.

Results: We analyzed the genotype-phenotype correlations in 275 CMTX1 patients belonging to 162 families and carrying 87 distinct variants. Patients with variants affecting the transmembrane domains demonstrated significantly greater severity, as evidenced by a Charcot-Marie-Tooth Examination Score of 10.5, compared to 7.1 for those with intracellular domain variants and 8.7 for extracellular domain variants (p < 0.000). These patients also experienced an earlier age of onset, showed slower ulnar nerve conduction velocities and had more substantial loss of motor amplitude.

Conclusions: This study confirms the presence of a correlation between the mutated protein domain and the clinical phenotype. Patients with a variant in the transmembrane domains demonstrated a more severe clinical and electrophysiological profile. Consequently, the genotype could play a prognostic role in addition to its diagnostic role, and it will be essential to consider this in future clinical trials.

Keywords: CMTX; Charcot‐Marie‐Tooth; clinical trial; connexine 32; hereditary peripheral neuropathy.

FIGURE 1

Schema c diagram of gap junction protein beta 1 and GJB variants in our cohort, from Bone et al. [16] and Barbat du Closel [15]. All reported missense, nonsense and frameshift GJB1 mutations are indicated with a colored circle. The five variants in the non‐coding regions and the complete coding sequence deletion (c.1_852del) are not indicated. C term, C‐terminal domain; EC, extracellular domain; IC, intracellular domain; N term, N‐terminal domain; TM, transmembrane.

FIGURE 2

(a) Charcot‐Marie‐Tooth Examination Score (CMTES) and (b) Overall Neuropathy Limitation Score (ONLS) of patients carrying a missense variant, by their mutated protein domain. Transmembrane domains (TM) are depicted with stripes. * Significance at <0.05, ** <0.01. C term, C‐terminal domain; EC, extracellular domain; IC, intracellular domain; N term, N‐terminal domain.

FIGURE 3

Phenotype of missense variants causing X‐linked Charcot‐Marie‐Tooth disease, by structural domain of the connexin 32. Intracellular domain (IC), including N‐terminal domain: AA 1‐19; IC: AA 93‐130 and C‐terminal domain: AA 208‐283; transmembrane domain (TM), including first TM (TM 1): AA 20‐38, second TM (TM 2): AA 74‐92, third TM (TM 3): AA 131‐148 and fourth TM (TM 4): AA 188‐207. Extracellular domain (EC), including first EC (EC 1): AA 39‐73 and second EC (EC 2): AA 149‐187. * Significance at <0.05, ** <0.01, *** <0.001. CMAP, compound muscle action potential; CMTES, Charcot‐Marie‐Tooth Examination Score; MNCV, motor nerve conduction velocity; ONLS, Overall Neuropathy Limitation Score.

FIGURE 4

American College of Medical Genetics classification of variants reported on (a) ClinVar or (b) based on their interpretation on Franklin Genoox. VUS, variants of uncertain significance.