| Summary: | Mitochondria are dynamic organelles undergoing continuous fusion and fission with Drp1, encoded by the <i>DNM1L</i> gene, required for mitochondrial fragmentation. <i>DNM1L</i> dominant pathogenic variants lead to progressive neurological disorders with early exitus. Herein we report on the case of a boy affected by epileptic encephalopathy carrying two heterozygous variants (<i>in cis</i>) of the <i>DNM1L</i> gene: a pathogenic variant (PV) c.1085G>A (p.Gly362Asp) accompanied with a variant of unknown significance (VUS) c.1535T>C (p.Ile512Thr). Amplicon sequencing of the mother’s DNA revealed the presence of the PV and VUS in 5% of cells, with the remaining cells presenting only VUS. Functional investigations performed on the patient and his mother’s cells unveiled altered mitochondrial respiratory chain activities, network architecture and Ca<sup>2+</sup> homeostasis as compared with healthy unrelated subjects’ samples. Modelling Drp1 harbouring the two variants, separately or in combination, resulted in structural changes as compared with Wt protein. Considering the clinical history of the mother, PV transmission by a maternal germline mosaicism mechanism is proposed. Altered Drp1 function leads to changes in the mitochondrial structure and bioenergetics as well as in Ca<sup>2+</sup> homeostasis. The novel VUS might be a modifier that synergistically worsens the phenotype when associated with the PV.
|
|---|
