The clinical utility of rapid exome sequencing in a consanguineous population
Authors: Monies Dorota , Goljan Ewa ,   Rapid Exome Consortium, Binmanee Abdulaziz Mohammed , Alashwal Abdullah Ali Zafir , Alsonbul Abdullah Mohammed , Alhussaini Abdulrahman A. , Abdallah Alahmari Ali , Albenmousa Ali Hussain , Almehaidib Ali Ibrahim , Hassan Ali Syed Akhtarul , Alharbi Amal Salman Alseraihy , Alhabib Amro , Podda Antonello , Alsaleem Badr , Al Saud Bandar Bin Khalid , Bin Abbas Bassam Saleh , Faqeih Eissa Ali , Aljofan Fahad Badei , Alhazzani Fahad Naser , Alrowaily Fouzah Awadh , Alzaidan Hamad Ibrahim , Almousa Hamoud Abdulkareem , Alsaedi Hawazen Saleh , Ghemlas Ibrahim Abdulaziz , Alsaleem Khalid Abdulrahman , Saleh Mahasen , Alghamdi Malak , Shams Marwa , Alabdulsalam Moath , Bayoumy Mohamed Salaheldin , Shagrani Mohammad Ali , Alowain Mohammed Abdulaziz , Ayas Mouhab Fakhreddine , Qasim Muhammad , Alshammari Muneera J. , Qadi Najeeb Shafat , Alzahrani Ohoud Saleh , Arnaout Rand K. H. , Alhamad Reem , Mohammed Reem Walid , Altassan Ruqaiah Saleh , Alghamdi Saad Ali , Khan Saadiya Javed , Alalaiyan Saleh Abdulrahman , Khan Sameena , Albuhairi Sultan Ibrahim , Algoufi Talal Turki , Alayed Tareq Mohammed , Alofisan Tari , Aldekhail Wajeeh Mohamed , Alhamoudi Waleed , Kurdi Wesam Ibrahim Yousef , Rahbeeni Zuhair Abdalla , Assoum Mirna , Albreacan Muna , Binhumaid Faisal , Subhani Shazia , Boureggah Abdulmlik , Hashem Mais , Abdulwahab Firdous , Abuyousef Omar , Temsah Mohamad H. , Alsohime Fahad , Kelaher James , Abouelhoda Mohamed , Meyer Brian F. , Alkuraya Fowzan S. 
Published: June 2023

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.