One PMP22/MPZ and Three MFN2/GDAP1 Concomitant Variants Occurred in a Cohort of 189 Chinese Charcot-Marie-Tooth Families

Abstract

Background and AimsCharcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies. The wide phenotypic variability may not be completely explained by a single mutation.Aims and MethodsTo explore the existence of concomitant variants in CMT, we enrolled 189 patients and performed molecular diagnosis by application of next-generation sequencing combined with multiplex ligation-dependent probe amplification. We conducted a retrospective analysis of patients harboring coinherited variants in different genes.ResultsFour families were confirmed to possess variants in two genes, accounting for 2.1% (4/189) of the total in our cohort. One CMT1 patient with PMP22 duplication and MPZ variant (c.286A>C, p.K96Q) exhibited moderate neuropathy with infantile onset, while her father possessing MPZ variant was mildly affected with adolescence onset. A CMT2 patient with heterozygous variants in MFN2 (c.613_622delGTCACCACAG, p.V205Sfs*26) and GDAP1 (c.713G>T, p.W238L) exhibited childhood onset mild phenotype, while his mother with MFN2 variant developed bilateral pes cavus only. A CMT2 patient with heterozygous variants in MFN2 (c.839G>A, p.R280H) and GDAP1 (c.3G>T, p.M1?) presented infantile onset and rapid progression, while her father with MFN2 variant presented with absence of deep tendon reflexes. One sporadic CMT2 patient with early onset was confirmed harboring de novo MFN2 variant (c.1835C>T, p.S612F) and heterozygous GDAP1 variant (c.767A>G, p.H256R).ConclusionOur results suggest that the possibility of concomitant variants was not uncommon and should be considered when significant intrafamilial clinical heterogeneity is observed.

Genetic and clinical profile of 15 Chinese families with GDAP1‐related Charcot–Marie–Tooth disease and identification of H256R as a frequent mutation

“…3 Studies have revealed that AD-inherited mutant forms of GDAP1 gain an abnormal function that impairs mitochondrial fusion, increases reactive oxygen species production, and initiates apoptosis, 23 Based on the available clinical data, the majority of GDAP1- in families with the R120W mutation 13 and the association of concomitant variants in GDAP1 and MFN2 with a more severe phenotype. 25 Therefore, these possibilities should be considered when significant clinical heterogeneity is observed, emphasizing the importance of comprehensive genetic counseling associated with genetic testing.…”

“…Furthermore, the co‐existence of Q38R in the proband of Family 15 resulted in a more pronounced and severe phenotypic effect than the dominant variant V219G inherited from her family. Previous studies have also reported significant phenotypic variability in GDAP1 ‐related CMT such as reduced penetrance in families with the R120W mutation 13 and the association of concomitant variants in GDAP1 and MFN2 with a more severe phenotype 25 . Therefore, these possibilities should be considered when significant clinical heterogeneity is observed, emphasizing the importance of comprehensive genetic counseling associated with genetic testing.…”

The GDAP1 p.Glu222Lys Variant-Weak Pathogenic Effect, Cumulative Effect of Weak Sequence Variants, or Synergy of Both Factors?

“…In particular, the cumulative effect of GDAP1 and MFN2 gene sequence variants was established. [ 19 , 20 , 21 , 22 ]. Such a genetic interaction is observed when proteins encoded by mutated genes participate in the same process.…”

Caractéristiques cliniques et électrophysiologiques des femmes atteintes de la maladie de Charcot-Marie-Tooth liée à l’X

“…Il existe parfois des situations complexes ou plusieurs gènes peuvent être impliqués chez une même personne atteinte de CMT (13,14). Il est également possible qu'un fragment de chromosome soit dupliqué ou au contraire supprimé, pouvant entraîner des variations du nombre de copies des gènes présents sur ce fragment.…”