Lessons from a systematic review of family-based studies in ALS

ALS is genetically heterogeneous, with many causal genes identified through family-based gene-discovery studies. To evaluate this progress, we systematically reviewed these studies and identified unresolved genomic regions across five pedigrees. Reexamination resolved two pedigrees, nominating FUS and SYNE1 as the causal genes. The remaining three pedigrees exhibited linkage to four unresolved regions, which we reanalyzed using large-scale genetic datasets. We found no convincing evidence for new ALS-causing variants in these regions. These unresolved regions originated from complex pedigrees-consanguineous, isolated, or containing only a few affected individuals-whereas successful linkage was observed in larger, multigenerational families with ALS. Our findings confirm that family-based methods are robust in typical ALS pedigrees but lack power in small pedigrees with few affected individuals or in phenotypically heterogeneous families. Given these challenges and the rare-variant architecture of ALS, we propose a 'super-pedigree' framework to identify extended families with ALS to discover shared genetic risk factors and help develop gene-based therapies.