Distal hereditary motor neuronopathy‐7 (HMNR7) is an autosomal recessive VWA1‐related disorder characterized predominantly by distal motor involvement. A 41‐year‐old man with a history of childhood orthopedic surgery for foot deformities exhibited progressive distal weakness and muscle atrophy with lower limb predominance. Electrophysiological studies showed axonal sensorimotor involvement. Whole‐genome sequencing identified two novel
VWA1
variants in compound heterozygosity: c.1244 T>C [p.(L415P)], located in the fibronectin type III (FN3) domain, and c.455delG [p.(G152Afs*54)]. This report underscores the importance of comprehensive genome analysis including
VWA1
in patients with distal neuropathies, particularly when early‐onset foot deformities are present, and highlights the potential pathogenic relevance of missense variants within the second FN3 domain.
Toshiyuki Kakumoto, Kenta Orimo, T. Matsukawa et al.· Neurology and Clinical Neuro...· 0 citations
Germline variants in leukemia predisposition genes are increasingly detected in pediatric patients. Nevertheless, the rare variants identified in diagnostic samples may be misinterpreted without variant-level functional evaluation and cautious clinical interpretation. Whole-exome sequencing was performed on 28 individuals from five kindreds in which at least two children developed acute leukemia. Results identified a rare ETV6 variant, c.604C > G (p.Arg202Gly), in monozygotic twins with ETV6::RUNX1-positive B-cell precursor acute lymphoblastic leukemia. To support variant interpretation, HeLa-cell populations stably expressing FLAG-tagged wild-type ETV6 and p.Arg202Gly and the known loss-of-function control p.Pro214Leu were established. Subcellular localization was assessed via immunofluorescence microscopy with quantitative scoring. Transcriptional repression was evaluated using luciferase reporter assays driven by ETV6 target promoters (MMP3 and PF4). p.Arg202Gly predominantly showed nuclear localization comparable to WT, whereas p.Pro214Leu was enriched in the cytoplasm. In the reporter assays, similar to WT, p.Arg202Gly retained repression activity. Meanwhile, p.Pro214Leu failed to repress both reporters. The in-silico prediction of nuclear export sequences suggested an additional export signal in p.Pro214Leu, but not in p.Arg202Gly. Collectively, these findings indicate that p.Arg202Gly behaves as WT-like in the assays performed and do not support a loss-of-function effect. Our study emphasizes the importance of variant-level functional assessment for rare ETV6 variants to inform clinical interpretation and avoid overestimation of pathogenicity.
Ai Yamada, Shun Nagasawa, Midori Nakagawa et al.· Human Cell· 0 citations
The findings expand the clinical and genetic spectrum of SIGMAR1-associated disease and support its classification as dHMN rather than ALS, particularly in patients with dHMN accompanied by pyramidal features.
Kento Kodama, M. Ando, Y. Higuchi et al.· Journal of Neuromuscular Dis...· 0 citations
