Identity-by-descent to resolve reduced penetrance and advance gene discovery in neurodegenerative disease

Abstract Advances in sequencing technologies have transformed human genetics and accelerated disease gene discovery. Yet a causal mutation remains to be identified for many families with an inherited disease. Incomplete penetrance, genetic heterogeneity, and limited family history can complicate the binary classification of familial and sporadic disease. These challenges are amplified in late-onset diseases such as amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), where obscured inheritance patterns limit gene discovery opportunities and can confound clinical risk assessment. We evaluated whether identity-by-descent (IBD) analysis can uncover cryptic relatedness and mitigate the impact of incomplete penetrance on disease gene mapping and clinical interpretation. Genome-wide IBD inference was performed in an integrated cross-continent cohort of 3,524 individuals of European ancestry spanning the ALS-FTD neurodegenerative spectrum. IBD identified 793 pairs of 1st-6th degree relatives (siblings to second cousins once removed), of which 31.5% were previously unrecognised and 15.8% had differing clinical diagnoses. Among individuals recorded as “sporadic”, 5.5% of ALS and 15.9% of FTD were genetically related to another affected individual in the cohort, demonstrating that reduced penetrance masks a substantial proportion of heritable disease. Affected individuals with known ALS/FTD-associated genetic variants had balanced male-to-female ratios, irrespective of reported family history or IBD-inferred relatedness, whereas those without an identified disease-linked genetic variant retained the expected male predominance in ALS/FTD cohorts. IBD analysis identified multiple cross-continent founder networks for known ALS disease genes, including SOD1 and C9orf72, and created 73 new IBD-defined pedigrees from apparently unrelated probands, providing a framework for disease variant discovery in otherwise underpowered families. Using SOD1 mutation-positive families as a positive-control framework, we demonstrated that IBD-based pedigree expansion retained the known disease locus in distant relatives while reducing genome-wide candidate regions, supporting its application to unresolved ALS/FTD pedigrees. In an IBD-identified extended pedigree comprising five affected individuals, genome-wide variant filtering identified three rare variants within a chromosome 13q21.33 candidate locus shared IBD by four individuals and supported by multipoint linkage analysis. IBD-based detection of cryptic relatedness reveals genetic links between familial and apparent sporadic neurodegenerative disease, helping to resolve penetrance-related inheritance misclassification. By reconstructing extended pedigrees using IBD, this approach strengthens gene discovery and supporting variant pathogenicity while providing clinicians with clearer context for inherited risk and genetic counselling.