Poster Presentation 47th Lorne Genome Conference 2026

Reconstructing pedigrees from identity-by-descent for disease gene discovery (133317)

Lyndal Henden 1 , Sandrine Chan Moi Fat 1 , Andrew Smith 1 , Isabel Li 1 2 , Thomas J Nicholas 3 , Miran Mrkela 4 5 , Zoe Zussa 1 , Natalie Grima 1 , Emily P McCann 1 , Jennifer A Fifita 1 , Simon Topp 6 7 8 , Alfredo Iacoangeli 6 9 10 11 , Dominic B Rowe 1 12 , Garth A Nicholson 13 14 , Carol Dobson-Stone 15 16 , John B Kwok 17 18 , Olivier Piguet 17 19 , Glenda Halliday 17 18 , Claire Troakes 9 20 , Ammar Al-Chalabi 9 11 21 , Christopher E Shaw 8 22 , Richard H Roxburgh 4 23 , Matthew C Kiernan 24 , Roger Pamphlett 17 25 26 , Benoit Liquet-Weiland 2 27 , Allan F McRae 28 , Tian Lin 29 , Nigel G Laing 30 , Merrilee Needham 31 32 33 , David Schultz 34 , Susan Mathers 35 , Steve Vucic 36 , Robert Henderson 29 37 38 , Pamela McCombe 39 40 , Anjali K Henders 29 , Aaron R Quinlan 3 , Emma L Scotter 4 41 , Bradley Smith 9 20 , Ian P Blair 1 , Kelly L Williams 1
  1. Macquarie University Motor Neuron Disease Research Centre, Macquarie University, NSW, Australia
  2. School of Mathematical and Physical Sciences, Faculty of Science and Engineering, Macquarie University, Sydney, NSW, Australia
  3. Department of Human Genetics, University of Utah, Salt Lake City, UT, USA
  4. Centre for Brain Research, University of Auckland, Auckland, New Zealand
  5. School of Biological Sciences, University of Auckland, Auckland, New Zealand
  6. Department of Biostatistics and Health Informatics, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, United Kingdom
  7. Maurice Wohl Clinical Neuroscience Institute, King’s College London, Department of Basic and Clinical Neuroscience, London, United Kingdom
  8. UK Dementia Research Institute Centre at King’s College London, School of Neuroscience, King’s College London, Strand, London, United Kingdom
  9. Department of Basic and Clinical Neuroscience, Institute of Psychiatry, Psychology and Neuroscience, King’s College London, Denmark Hill, London, United Kingdom
  10. National Institute for Health Research Biomedical Research Centre and Dementia Unit at South London and Maudsley NHS Foundation Trust and King's College London, London, United Kingdom
  11. Perron Institute for Neurological and Translational Science, University of Western Australia Medical School, Perth, WA, Australia
  12. Multidisciplinary MND Clinic, Faculty of Medicine, Health and Human Sciences, Macquarie University, Macquarie Park, NSW, Australia
  13. Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, NSW, Australia
  14. Molecular Medicine Laboratory, Concord Repatriation General Hospital, Sydney, NSW, Australia
  15. Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia
  16. School of Medical Sciences, Faculty of Medicine and Health, The University of Sydney, Sydney, NSW, Australia
  17. Brain and Mind Centre, The University of Sydney, Sydney, NSW, Australia
  18. School of Medical Sciences, Faculty of Medicine and Health, University of New South Wales, Sydney, NSW, Australia
  19. School of Psychology, Faculty of Science, The University of Sydney, Sydney, NSW, Australia
  20. Centre for Developmental Neurobiology and MRC CNDD, Institute of Psychiatry, Psychology and Neuroscience, Guy’s Campus, King’s College London, London, United Kingdom
  21. King's College Hospital, Bessemer Road, Denmark Hill, London, United Kingdom
  22. Maurice Wohl Clinical Neurosciences, Institute of Psychiatry, Psychology and Neuroscience King’s College London, London, United Kingdom
  23. Department of Neurology, Auckland District Health Board, Auckland, New Zealand
  24. Neuroscience Research Australia, University of NSW, South Eastern Sydney Local Health District, Sydney, Australia
  25. Discipline of Pathology, The University of Sydney, Sydney, NSW, Australia
  26. Department of Neuropathology, Royal Prince Alfred Hospital, Sydney, NSW, Australia
  27. Laboratoire de Mathématiques et de leurs Applications UMR CNRS 5142, Université de Pau et des Pays de l'Adour, E2S-UPPA, Pau, France
  28. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  29. Institute for Molecular Bioscience, University of Queensland, QLD, Australia
  30. Harry Perkins Institute of Medical Research, and Centre for Medical Research, University of Western Australia, Nedlands, WA, Australia
  31. Fiona Stanley Hospital, Perth, WA, Australia
  32. Notre Dame University, Fremantle, WA, Australia
  33. Institute for Immunology and Infectious Diseases, Murdoch University, Perth, WA, Australia
  34. Neurology Department and MND Clinic, Flinders Medical Centre, Adelaide, SA, Australia
  35. Calvary Health Care Bethlehem, Parkdale, VIC, Australia
  36. Brain and Nerve Research Centre, Concord Clinical School, University of Sydney, Concord Hospital, Sydney, NSW, Australia
  37. Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
  38. Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
  39. Centre for Clinical Research, The University of Queensland, Brisbane, QLD, Australia
  40. Department of Neurology, Royal Brisbane and Women’s Hospital, Brisbane, QLD, Australia
  41. School of Biological Sciences, University of Auckland, Auckland, New Zealand

Background: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are neurodegenerative disorders with overlapping clinical, pathological and genetic features. Genetic factors are the only proven causes, yet identified variants explain disease in only ~15% of ALS and ~30% of FTD patients. Traditional gene discovery approaches, like linkage analysis for highly penetrant families and genome-wide association studies in sporadic cohort, have limited power in smaller or reduced-penetrance cohorts. Alternative strategies are needed to bridge the gap.

We use identity-by-descent (IBD) analysis as an alternative method for gene discovery in an integrated cohort of ALS and FTD cases. We hypothesis that IBD can uncover previously unknown relatives among affected individuals, enabling pedigree reconstruction and identification of shared inherited genomic regions for downstream variant discovery using whole-genome sequencing (WGS).

Methods: Pairwise IBD analysis was performed using XIBD (1) on SNP genotype data from ~3,500 ALS and FTD patients of European ancestry from Australia, New Zealand and the United Kingdom. Relationship degrees were estimated using KING (2). For one IBD-linked pedigree, short-read WGS was interrogated for SNVs, indels and repeat expansions (3,4) within shared IBD regions. Variants were validated using IGV (5) and REViewer (6).

Results: 793 pairs of 1st-6th degree relatives were identified, one-third of which were previously unknown, including ~5% of sporadic ALS and ~16% of sporadic FTD cases. We identified 76 IBD-linked pedigrees for gene discovery. Comparative genomics of one IBD pedigree revealed candidate variants within a shared locus (LOD = 3.3).

Conclusions: IBD inference enables pedigree reconstruction and variant discovery across heterogeneous ALS and FTD cohorts, providing a scalable strategy to uncover missing heritability beyond traditional methods.

  1. 1.Henden L, et al. Bioinformatics. 2016;32:2389–2391.
  2. 2.Manichaikul A, et al. Bioinformatics. 2010;26:2867–2873.
  3. 3.Dolzhenko E, et al. Bioinformatics. 2019;35(22):4754-4756.
  4. 4.Dolzhenko E, et al. Genome Biol. 2020;21(1):102.
  5. 5.Robinson JT, et al. Nat Biotechnol. 2011;29:24–26.
  6. 6.Dolzhenko E, et al. Genome Med. 2022;14:84.