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Publications

Journal Article Ppublish

PubMed: 42434812 DOI: 10.1016/j.gim.2026.102661

High-throughput evidence generation to support tentative gene-disease relationship from a cohort enriched for autozygosity and founder effect.

Genet Med 28(10):102661

Authors: Khadijah Bakur, Bader Alhaddad, Ali Balubaid, Syed Makki, Sarar Mohamed, Fuad Al Mutairi, Abdulrahman Alswaid, Malak Al Ghamdi, Talal Alanzi, Wafaa Eyaid, Mohammed A Almuqbil, Mohammed A Mahnashi, Maha Al-Otaibi, Ali Awaji, Dalal K Bubshait, Walaa Alshuaibi, Ruqaiah Altassan, Ghadah Gosadi, Elham Almardawi, Abduljabbar Alshenqiti, Abdullah Al Faifi, Bassam Bin Abbas, Mohammad A Al-Muhaizea, Hamad AlZaidan, Mohammed Al-Owain, Maryam Busehail, Aaisha Al Balushi, Basma Ali Abadel, Maryam Al Shehhi, Amal Al Tenaiji, Abdullah Al-Nawfal, Moayed Aljack, Ahmed AlBadawi, Halima Hamid, Maha Al Shalan, Modhi Alotaibi, Hala Alathel, Fahad Algaeed, Mohthash Musambil, Hamzah Naji, Shatha Alhefdhi, Hadeel Alrabee, Maha Al Harbi, Fahad Hakami, Manal Abothnain, Jameela A Kari, Mohamed A Shalaby, Nabil Almajhad, Hanan Baarma, Brahim Tabarki … and 46 other authors

Affiliations

  • Lifera Omics, Riyadh, Saudi Arabia.
  • Department of Genetics and Metabolic Medicine, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia; Department of Pediatrics, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Faculty of Medicine, National University, Khartoum, Sudan.
  • Medical Genomic Research Department, King Abdullah International Medical Research Center (KAIMRC), King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia; Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.
  • Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia; King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
  • Medical Genetics Division, Department of Pediatrics, King Saud University Medical City, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Genetic Clinical Service, Research & Scientific Center, Sultan Bin Abdulaziz Humanitarian City, Riyadh, Saudi Arabia.
  • Women and Children's Health Department, Johns Hopkins Aramco Healthcare Center, Dhahran, Saudi Arabia.
  • College of Medicine, King Saud Bin Abdulaziz University for Health Sciences (KSAU-HS), Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard, Riyadh, Saudi Arabia; Division of Pediatric Neurology, Department of Pediatrics, King Abdullah Specialist Children's Hospital (KASCH), National Guard Health Affairs (NGHA), Riyadh, Saudi Arabia.
  • King Fahad Central Hospital, Jazan, Saudi Arabia.
  • Department of Medical Genetics, King Saud Medical City, Riyadh, Saudi Arabia.
  • Medical Genetic and Metabolic Department, Prince Mohammed Bin Nasser Hospital, Jazan, Saudi Arabia.
  • Department of Pediatrics, College of Medicine, King Fahd Hospital of the University, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia.
  • Medical Genetics Division, Department of Pediatrics, King Saud University Medical City, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
  • Medical Genomic Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • Department of Obstetrics and Gynecology, Security Forces Hospital, Riyadh, Saudi Arabia.
  • King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia; King Abdullah International Medical Research Center (KAIMRC), Ministry of National Guard, Riyadh, Saudi Arabia; Department of Pediatrics, Prince Mohammed Bin Abdulaziz Hospital, Ministry of National Guard-Health Affairs, Al-Madinah, Saudi Arabia.
  • Security Forces Hospital, Riyadh, Saudi Arabia.
  • Section of Pediatric Endocrinology, Department of Pediatrics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
  • Neuroscience Centre, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • Medical Genomic Department, Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia; Department of Anatomy and Genetics, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia.
  • Government Hospitals, Arabian Gulf University, Manama, Bahrain.
  • National Genetic Center, Royal Hospital, Muscat, Oman.
  • Department of Pediatrics, Division of Clinical Genetics and Metabolic Disorders, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia.
  • Division of Genetics and Metabolic Medicine, Pediatrics Department, Sheikh Khalifa Medical City, PureHealth/SEHA and UAE University, Abu Dhabi, UAE.
  • Genetics and Precision Medicine Department (GPM), King Abdullah Specialized Children's Hospital (KASCH), King Abdulaziz Medical City, Ministry of National Guard Health Affairs (MNG-HA), Riyadh, Saudi Arabia.
  • Genetics Department, Thuriah Medical Center, Riyadh, Saudi Arabia.
  • Department of Genetics and Metabolic Medicine, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.
  • Center for Genetic Diseases, Ministry of Health, Al-Qassim Region, Saudi Arabia.
  • King Abdullah International Research Center, King Abdulaziz Medical City, Jeddah, Saudi Arabia.
  • Pediatric Nephrology Centre of Excellence, King Abdulaziz University Hospital and Nephrology Unit, Pediatric Department, King Abdulaziz University, Jeddah, Saudi Arabia.
  • Department of Pediatrics, Division of Pediatric Neurology, Maternity and children Hospital, Alhassa, Saudi Arabia.
  • Division of Pediatric Neurology, Department of Pediatrics, King Fahad Armed Forces Hospital, Jeddah, Saudi Arabia.
  • Division of Neurology, Department of Pediatrics, Prince Sultan Military Medical City, Riyadh, Saudi Arabia.

Abstract

PURPOSE

Gene-disease relationship (GDR) is a key concept in monogenic disease diagnostics. Although functional analysis and disease modeling play important supporting roles, human genetics evidence remains key to supporting or challenging a proposed GDR. Such evidence typically comes from individual publications that address one GDR at a time. We hypothesized that a large cohort composed primarily of Mendelian phenotypes and enriched for consanguinity and founder effect can accelerate evidence generation by enabling high-throughput discovery of homozygous loss-of-function (LOF) variants as well as strong segregation data.

METHODS

To test this hypothesis, we analyzed our Lifera Omics Database (LODB) for homozygous high-impact missense variants that are observed in 2 or more unrelated individuals to exploit the power of founder variants, as well as homozygous presumptive LOF variants. The search spanned 2904 genes with tentative GDRs in the literature.

RESULTS

The analysis revealed 154 individuals with 119 homozygous LOF variants that support GDRs for 95 genes. Additionally, we identified 13 founder missense variants (33 homozygous individuals) that support GDR for 13 genes. Our data expand the mode of inheritance (MOI) of 19 genes for which the tentative GDRs were based on dominant variants. Phenotypic expansion was encountered in 18 of the supported GDRs, including those in which the full syndromic constellation has not been previously delineated. We also report four novel allelic disorders of reported GDRs.

CONCLUSION

This work highlights the potential of diagnostic laboratories to accelerate GDR refinement through data sharing and working closely with referring physicians. It also showcases the added advantage concerning autosomal recessive GDR when the study population is enriched for consanguinity and founder effect.

MeSH

Genes, Founder Effect, Work, Consanguinity