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

BACKGROUND AND AIMS

Charcot-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 METHODS

To 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.

RESULTS

Four 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 duplication and variant (c.286A>C, p.K96Q) exhibited moderate neuropathy with infantile onset, while her father possessing variant was mildly affected with adolescence onset. A CMT2 patient with heterozygous variants in (c.613_622delGTCACCACAG, p.V205Sfs26) and (c.713G>T, p.W238L) exhibited childhood onset mild phenotype, while his mother with variant developed bilateral only. A CMT2 patient with heterozygous variants in (c.839G>A, p.R280H) and (c.3G>T, p.M1?) presented infantile onset and rapid progression, while her father with variant presented with absence of deep tendon reflexes. One sporadic CMT2 patient with early onset was confirmed harboring variant (c.1835C>T, p.S612F) and heterozygous variant (c.767A>G, p.H256R).

CONCLUSION

Our results suggest that the possibility of concomitant variants was not uncommon and should be considered when significant intrafamilial clinical heterogeneity is observed.