Identifying individuals with rare disease variants by inferring shared ancestral haplotypes from SNP array data

We describe FoundHaplo, a novel identity-by-descent algorithm designed to identify individuals with known, untyped, disease-causing variants using only SNP array data. FoundHaplo leverages knowledge of shared disease haplotypes for inherited disease-causing variants to identify individuals who share the disease haplotype and are, therefore, likely to carry the rare (MAF<0.01) variant. We performed a simulation study to evaluate the performance of FoundHaplo across 33 known disease-harbouring loci. We demonstrated the ability of FoundHaplo to infer the presence of two rare (MAF<0.01) pathogenic variants, SCN1B c.363C>G (p.Cys121Trp) and WWOX c.49G>A (p.E17K), which can cause mild dominant and severe recessive epilepsy respectively, in two large cohorts including 1,573 individuals with epilepsy from the Epi25 cohort and 468,481 individuals from the UK Biobank. We demonstrate that FoundHaplo performs substantially better at inferring the presence of these variants than existing genome-wide imputation approaches. FoundHaplo is a valuable, low-cost screening tool that can be applied to search SNP genotyping array data for disease-causing variants with known founder effects based on shared disease haplotypes. FoundHaplo is available at . ### Competing Interest Statement Ingrid Scheffer has served on scientific advisory boards for BioMarin, Chiesi, Eisai, Encoded Therapeutics, GlaxoSmithKline, Knopp Biosciences, Nutricia, Rogcon, Takeda Pharmaceuticals, UCB, Xenon Pharmaceuticals, Cerecin; has received speaker honoraria from GlaxoSmithKline, UCB, BioMarin, Biocodex, Chiesi, Liva Nova, Nutricia, Zuellig Pharma, Stoke Therapeutics and Eisai; has received funding for travel from UCB, Biocodex, GlaxoSmithKline, Biomarin, Encoded Therapeutics, Stoke Therapeutics and Eisai; has served as an investigator for Anavex Life Sciences, Cerevel Therapeutics, Eisai, Encoded Therapeutics, EpiMinder Inc, Epygenyx, ES-Therapeutics, GW Pharma, Marinus, Neurocrine BioSciences, Ovid Therapeutics, Takeda Pharmaceuticals, UCB, Ultragenyx, Xenon Pharmaceuticals, Zogenix and Zynerba; and has consulted for Care Beyond Diagnosis, Epilepsy Consortium, Atheneum Partners, Ovid Therapeutics, UCB, Zynerba Pharmaceuticals, BioMarin, Encoded Therapeutics and Biohaven Pharmaceuticals; and is a Non-Executive Director of Bellberry Ltd and a Director of the Australian Academy of Health and Medical Sciences and the Australian Council of Learned Academies Limited. She may accrue future revenue on pending patent WO61/010176 (filed: 2008): Therapeutic Compound; has a patent for SCN1A testing held by Bionomics Inc and licensed to various diagnostic companies; has a patent molecular diagnostic/theranostic target for benign familial infantile epilepsy (BFIE) [PRRT2] 2011904493 & 2012900190 and PCT/AU2012/001321 (TECH ID:2012-009). ### Funding Statement Funding support was provided by an Australian National Health and Medical Research Council (NHMRC) Investigator grant APP1195236 (MB); an NHMRC Senior Investigator Grant \[GNT1172897\] (IES); an NHMRC Senior Investigator Grant \[APP196637\] (SFB); a Melbourne Research Scholarship (392655) (ER); a CURE Epilepsy Taking Flight Award (MFB); an Australian Government Research Training Program Scholarship APP533086 (KLO); DHB Foundation Centenary Postdoctoral Fellowship in Neurogenetic Systems Biology (LGF); Health Research Council of New Zealand and Cure Kids (LS). The Victorian Government Operational Infrastructure Support Program and the NHMRC Independent Research Institute Infrastructure Support Scheme also supported this work. We would also like to acknowledge Professor Jozef Gecz and Dr Mark Corbett for valuable discussions on early work. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study was approved by the Austin Health Human Research Ethics Committee. Informed consent was obtained and archived from all participants or their legal guardian. Research was approved by the Human Research Ethics Committee at The Walter and Eliza Hall Institute of Medical Research. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes This research has been conducted using data from UK Biobank, a major biomedical database. The UK Biobank is an open access resource. To access the UKBB datasets, you need to register as a UKBB researcher (https://www.ukbiobank.ac.uk/enable-your-research/register). Additional genetic data used in this study is not available due to patient privacy and ethical restrictions. FoundHaplo is available at https://github.com/bahlolab/FoundHaplo.