A Framework For Large-Scale Reconstruction Of Extended Pedigrees To Facilitate Gene Discovery In ALS

Importance: With emerging gene-targeted therapies in amyotrophic lateral sclerosis (ALS), gene discoveries and genetic diagnoses provide a crucial path to treatment. Pathogenic variants with moderate effect or incomplete penetrance, however, remain unidentified in genome-wide association studies and can appear sporadic in small modern-day pedigrees. Lack of recognition of familial clustering of ALS, in turn, limits opportunities for gene discovery, genetic diagnosis, risk counseling, and treatment. Objective: To determine the power of automated reconstruction of extended pedigrees, integrating archive records and genetic relatedness, in gene-discovery studies. Design: Retrospective observational study of Dutch ALS patients with the C9orf72 hexanucleotide repeat expansion (HRE), combining clinical family history, civil records, and genome-wide genotyping for relatedness and identity-by-descent (IBD) inference. Setting: National, population-based ALS cohort from the Netherlands and digitized population archives enabling systematic reconstruction of extended pedigrees. Participants: Individuals with ALS and a confirmed C9orf72 HRE. Participants must have provided a clinical family history and traceable Dutch ancestry documented in population archives. Main Outcomes and Measures: The primary outcome was the proportion of C9orf72 HRE carriers with newly identified (distant) relatives with ALS compared with clinical family history. The secondary outcome was the precision of IBD-based methods to fine-map the C9orf72 HRE. Other outcomes included phenotypic similarities between distantly related patients. Results: Among 238 C9orf72 HRE carriers, 91 could be included in one of 39 extended pedigrees dating back to ~1800, with relationships up to the eighth degree of relatedness. Compared with clinical family history alone, our approach increased the number of identified relationships by 2.5-fold. Genome-wide IBD analysis revealed shared haplotypes encompassing the C9orf72 HRE in 94% of pedigrees by [≥]7 meioses in 25.7-127.8 centimorgans total IBD shared. Conclusions and Relevance: Large-scale interrogation of archives facilitates reconstruction of extended pedigrees for ALS patients carrying the C9orf72 HRE. This combined genealogical-genetic approach supports the reclassification of apparently sporadic cases, facilitates the discovery of new disease-causing variants in ALS, and is generalizable to other late-onset neurodegenerative diseases. Automated pedigree reconstruction from genealogical data and visualization in an interactive databrowser are implemented in the open-source Mangrove software.