High-throughput evidence generation to support tentative gene-disease relationship from a cohort enriched for autozygosity and founder effect.
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Bakur Khadijah, Alhaddad Bader, Balubaid Ali, Makki Syed, Mohamed Sarar, Al Mutairi Fuad, Alswaid Abdulrahman, Al Ghamdi Malak, Alanzi Talal, Eyaid Wafaa, Almuqbil Mohammed A, Mahnashi Mohammed A, Al-Otaibi Maha, Awaji Ali, Bubshait Dalal K, Alshuaibi Walaa, Altassan Ruqaiah, Gosadi Ghadah, Almardawi Elham, Alshenqiti Abduljabbar, Al Faifi Abdullah, Abbas Bassam Bin, Al-Muhaizea Mohammad A, AlZaidan Hamad, Al-Owain Mohammed, Busehail Maryam, Al Balushi Aaisha, Abadel Basma Ali, Al Shehhi Maryam, Al Tenaiji Amal, Al-Nawfal Abdullah, Aljack Moayed, AlBadawi Ahmed, Hamid Halima, Al Shalan Maha, Alotaibi Modhi, Alathel Hala, Algaeed Fahad, Musambil Mohthash, Naji Hamzah, Alhefdhi Shatha, Alrabee Hadeel, Al Harbi Maha, Hakami Fahad, Abothnain Manal, Kari Jameela A, Shalaby Mohamed A, Almajhad Nabil, Baarma Hanan, Tabarki Brahim, Al Masseri Zainab, Sulaiman Raashda A, Ababneh Faroug, Abukhaled Musaad, Bashaikh Afnan, AlGarni Abdulaziz Mohammed, Alghamdi Khalid A, Alsowat Daad, Alfarsi Anar, Habhab Wisam, AlAali Wajeih, Tulbah Maha I, AlTaifi Hatoon Ahmed, Almubayedh Sondos, Alsalamah Abrar K, Alqassmi Amal, Abdullah Sameer, Al Tala Saeed, Howsawi Yousef, Alhumaidi Suzan Suliman, Shok Ahmed Abkar, Alwadei Ali H, Shagrani Mohammad, Alkuraya Hisham, Alshaya Wael, Abumansour Iman Sabri, Mushiba Aziza M, Algethami Albandari, Assiri Asma, Ba-Abbad Rola, Alaskar Ahmed S, Almoallem Basamat, Al Mahroos Marwa, Alanazi Rola, Alanezi Ahmad A, Albert-Brotons Dimpna C, Alhashem Amal, Alatawi Mona, Ben-Omran Tawfeg, Alsagheir Afaf, Kaya Namik, Maddirevula Sateesh, Baalawi Wail, Alfadhel Majid, AlAbdi Lama, Alkuraya Fowzan S
Аннотация
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.