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Identification of co-segregating RUBCN and KANK1 mutations in a UK amyotrophic lateral sclerosis kindred
medRxiv · · Preprint · Open access
Salman, Bakhtiar + 6 more
Abstract ↗AI summary
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In a United Kingdom ALS kindred, ultra-rare RUBCN p.Cys517Phe and KANK1 p.Pro1332Ala variants co-segregate with disease, with FLB scores 4.6 and 5.5.
- Why it matters: ALS genetics still lacks fully validated causal genes, and this work targets a family-based signal plus population and functional evidence to strengthen candidate gene links.
- What they did: Next-generation sequencing and likelihood-based segregation testing were used, with FLB thresholds for pathogenicity (≥4.33) and sex-stratified penetrance modeling; independent cohort burden used SKAT-O (p < 1 x 10-9).
- The result: Carrier lymphoblastoid cells showed increased apoptosis and pathway dysregulation (p < 0.05), while ALS spinal cord had RUBCN upregulation 2.85-fold and KANK1 downregulation 0.40-fold (p < 0.05).
The findingWhy it mattersWhat they didThe result
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- Open access