The clinical utility of rapid exome sequencing in a consanguineous population
Dorota Monies, Ewa Goljan, Abdulaziz Binmanee, Abdullah Al‐Ashwal, Abdullah Alsonbul, Abdulrahman Al‐Hussaini, Alahmari Ali Abdallah, Ali Albenmousa, Ali Almehaidib, Ali Hassan, Amal Salman Alseraihy Alharbi, Amro Al-Habib, Antonello Podda, Badr Alsaleem, Bandar Bin Khalid Al Saud, Bassam Saleh Bin Abbas, Eissa Faqeih, Fahad Aljofan, Fahad Naser Alhazzani, Fouzah Awadh Alrowaily, Hamad Alzaidan, Hamoud Al‐Mousa, Hawazen Saleh Alsaedi, Ibrahim Abdulaziz Ghemlas, Khalid A. Alsaleem, Mahasen Saleh, Malak Alghamdi, M Shams, Moath Alabdulsalam, Mohamed Bayoumy, Mohammad Shagrani, Mohammed Al‐Owain, Mouhab Ayas, Muhammad Qasim, Muneera Alshammari, Najeeb Qadi, Ohoud Alzahrani, Rand Arnaout, Reem Alhamad, Reem Mohammed, Ruqaiah Altassan, Saad Alghamdi, Saadiya Khan, Saleh Al‐Alaiyan, Sameena Khan, Sultan Albuhairi, Talal Turki Algoufi, Tareq Alayed, Tari Alofisan, Wajeeh Aldekhail, Waleed Al–Hamoudi, Wesam Kurdi, Zuhair Abdalla Rahbeeni, Mirna Assoum, Muna Albreacan, Faisal S. BinHumaid, Shehryar Subhani, Abdulmlik Boureggah, Mais Hashem, Firdous Abdulwahab, Omar Abuyousef, Mohamad‐Hani Temsah, Fahad Alsohime, James Kelaher, Mohamed Abouelhoda, Brian F. Meyer, Fowzan S. Alkuraya
Abstract
BACKGROUND: The clinical utility of exome sequencing is now well documented. Rapid exome sequencing (RES) is more resource-intensive than regular exome sequencing and is typically employed in specialized clinical settings wherein urgent molecular diagnosis is thought to influence acute management. Studies on the clinical utility of RES have been largely limited to outbred populations. METHODS: Here, we describe our experience with rapid exome sequencing (RES) in a highly consanguineous population. Clinical settings included intensive care units, prenatal cases approaching the legal cutoff for termination, and urgent transplant decisions. RESULTS: A positive molecular finding (a pathogenic or likely pathogenic variant that explains the phenotype) was observed in 80 of 189 cases (42%), while 15 (8%) and 94 (50%) received ambiguous (variant of uncertain significance (VUS)) and negative results, respectively. The consanguineous nature of the study population gave us an opportunity to observe highly unusual and severe phenotypic expressions of previously reported genes. Clinical utility was observed in nearly all (79/80) cases with positive molecular findings and included management decisions, prognostication, and reproductive counseling. Reproductive counseling is a particularly important utility in this population where the overwhelming majority (86%) of identified variants are autosomal recessive, which are more actionable in this regard than the de novo variants typically reported by RES elsewhere. Indeed, our cost-effectiveness analysis shows compelling cost savings in the study population. CONCLUSIONS: This work expands the diversity of environments in which RES has a demonstrable clinical utility.