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, Zainab Al Masseri, Raashda A Sulaiman, Faroug Ababneh, Musaad Abukhaled, Afnan Bashaikh, Abdulaziz Mohammed AlGarni, Khalid A Alghamdi, Daad Alsowat, Anar Alfarsi, Wisam Habhab, Wajeih AlAali, Maha I Tulbah, Hatoon Ahmed AlTaifi, Sondos Almubayedh, Abrar K Alsalamah, Amal Alqassmi, Sameer Abdullah, Saeed Al Tala, Yousef Howsawi, Suzan Suliman Alhumaidi, Ahmed Abkar Shok, Ali H Alwadei, Mohammad Shagrani, Hisham Alkuraya, Wael Alshaya, Iman Sabri Abumansour, Aziza M Mushiba, Albandari Algethami, Asma Assiri, Rola Ba-Abbad, Ahmed S Alaskar, Basamat Almoallem, Marwa Al Mahroos, Rola Alanazi, Ahmad A Alanezi, Dimpna C Albert-Brotons, Amal Alhashem, Mona Alatawi, Tawfeg Ben-Omran, Afaf Alsagheir, Namik Kaya, Sateesh Maddirevula, Wail Baalawi, Majid Alfadhel, Lama AlAbdi, Fowzan S Alkuraya
Published in
Genetics in medicine : official journal of the American College of Medical Genetics. Pages 102661. Jul 10, 2026. Epub Jul 10, 2026.
Abstract
Gene-disease relationship (GDR) is a key concept in monogenic disease diagnostics. While functional analysis and disease modeling play important supporting roles, human genetics evidence remains key to support or challenge proposed GDR. Such evidence typically comes from individual publications that address one GDR at a time. We hypothesized that a large cohort comprised 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.
To test this hypothesis, we analyzed our Lifera Omics Database (LODB) for homozygous high impact missense variants that are observed in two or more unrelated individuals to exploit the power of founder variants, as well as homozygous presumptive LOF. The search spanned 2,904 genes with tentative GDR in the literature.
The analysis revealed 154 individuals with 119 homozygous LOF variants that support GDR 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 GDR was based on dominant variants. Phenotypic expansion was encountered in 18 of the supported GDR including those in which the full syndromic constellation has not been previously delineated. We also report 4 novel allelic disorders of reported GDR.
This work highlights the potential of diagnostic labs to accelerate GDR refinement through data sharing and working closely with the referring physicians. It also showcases the added advantage concerning autosomal recessive GDR when the study population is enriched for consanguinity and founder effect.
PMID:
42434812
Bibliographic data and abstract were imported from PubMed on 11 Jul 2026.
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