CMT : when the NGS comes to both simplify and complicate things

Charcot-Marie-Tooth (or CMT) type hereditary sensory-motor neuropathies are clinically and genetically heterogeneous pathologies affecting all ages and all sexes. Relatively frequent in the general population, they have in common that they result in a variable scalability deficit in the muscles of limbs extremities (hands, feet) and sometimes very discreet sensory disorders. More than 80 genes are responsible for this, whether they are demyelinating forms (CMT1) or axonal forms (CMT2). While high-throughput sequencing (NGS) has greatly facilitated genotyping, it increasingly leads to difficult interpretive observations. 


French specialists report the case of a family in which several sequence variants coexist corresponding to several subtypes of CMT. A mother and her daughter both presented a deficit compatible with a classic CMT2. The girl’s clinical examination, however, revealed the presence of other neurological signs such as nystagmus and dystonia. Genotyping revealed within the extended family three sequence variants in three distinct genes (MFN2, MORC2 and AARS1). This observation constitutes a new example of the difficulty of interpreting the results of NGS studies but also of the frequency, certainly underestimated, of cases of di- or tri-genism in many genetic diseases including CMT.


One Multilocus Genomic Variation Is Responsible for a Severe Charcot-Marie-Tooth Axonal Form. F Miressi, C Magdelaine, P Cintas et al. Brain Sci. 2020 (Dec).