Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population

Dorota Monies 1, Mohammed Abouelhoda 1, Mirna Assoum 2, Nabil Moghrabi 1, Rafiullah Rafiullah 2, Naif Almontashiri 3, Mohammed Alowain 4, Hamad Alzaidan 4, Moeen Alsayed 4, Shazia Subhani 1, Edward Cupler 5, Maha Faden 6, Amal Alhashem 7, Alya Qari 4, Aziza Chedrawi 8, Hisham Aldhalaan 8, Wesam Kurdi 9, Sameena Khan 8, Zuhair Rahbeeni 4, Maha Alotaibi 6, Ewa Goljan 1, Hadeel Elbardisy 2, Mohamed ElKalioby 10, Zeeshan Shah 1, Hibah Alruwaili 1, Amal Jaafar 1, Ranad Albar 11, Asma Akilan 2, Hamsa Tayeb 1, Asma Tahir 1, Mohammed Fawzy 1, Mohammed Nasr 1, Shaza Makki 2, Abdullah Alfaifi 12, Hanna Akleh 13, Suad Yamani 8, Dalal Bubshait 14, Mohammed Mahnashi 15, Talal Basha 16, Afaf Alsagheir 17, Musad Abu Khaled 8, Khalid Alsaleem 17, Maisoon Almugbel 9, Manal Badawi 8, Fahad Bashiri 18, Saeed Bohlega 8, Raashida Sulaiman 4, Ehab Tous 8, Syed Ahmed 19, Talal Algoufi 19, Hamoud Al-Mousa 20, Emadia Alaki 20, Susan Alhumaidi 21, Hadeel Alghamdi 16, Malak Alghamdi 21, Ahmed Sahly 17, Shapar Nahrir 21, Ali Al-Ahmari 22, Hisham Alkuraya 23, Ali Almehaidib 24, Mohammed Abanemai 24, Fahad Alsohaibaini 24, Bandar Alsaud 20, Rand Arnaout 20, Ghada M H Abdel-Salam 25, Hasan Aldhekri 17, Suzan AlKhater 26, Khalid Alqadi 8, Essam Alsabban 17, Turki Alshareef 27, Khalid Awartani 9, Hanaa Banjar 28, Nada Alsahan 9, Ibraheem Abosoudah 29, Abdullah Alashwal 30, Wajeeh Aldekhail 24, Sami Alhajjar 31, Sulaiman Al-Mayouf 17, Abdulaziz Alsemari 8, Walaa Alshuaibi 32, Saeed Altala 33, Abdulhadi Altalhi 34, Salah Baz 8, Muddathir Hamad 32, Tariq Abalkhail 8, Badi Alenazi 35, Alya Alkaff 9, Fahad Almohareb 36, Fuad Al Mutairi 37, Mona Alsaleh 19, Abdullah Alsonbul 38, Somaya Alzelaye 39, Shakir Bahzad 40, Abdulaziz Bin Manee 17, Ola Jarrad 17, Neama Meriki 41, Bassem Albeirouti 42, Amal Alqasmi 21, Mohammed AlBalwi 43, Nawal Makhseed 44, Saeed Hassan 32, Isam Salih 45, Mustafa A Salih 18, Marwan Shaheen 46, Saadeh Sermin 27, Shamsad Shahrukh 5, Shahrukh Hashmi 46, Ayman Shawli 47, Ameen Tajuddin 48, Abdullah Tamim 49, Ahmed Alnahari 50, Ibrahim Ghemlas 19, Maged Hussein 51, Sami Wali 7, Hatem Murad 8, Brian F Meyer 1, Fowzan S Alkuraya 52

Affiliations

06 June 2019

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doi: 10.1016/j.ajhg.2019.04.011

Abstract

We report the results of clinical exome sequencing (CES) on >2,200 previously unpublished Saudi families as a first-tier test. The predominance of autosomal-recessive causes allowed us to make several key observations. We highlight 155 genes that we propose to be recessive, disease-related candidates. We report additional mutational events in 64 previously reported candidates (40 recessive), and these events support their candidacy. We report recessive forms of genes that were previously associated only with dominant disorders and that have phenotypes ranging from consistent with to conspicuously distinct from the known dominant phenotypes. We also report homozygous loss-of-function events that can inform the genetics of complex diseases. We were also able to deduce the likely causal variant in most couples who presented after the loss of one or more children, but we lack samples from those children. Although a similar pattern of mostly recessive causes was observed in the prenatal setting, the higher proportion of loss-of-function events in these cases was notable. The allelic series presented by the wealth of recessive variants greatly expanded the phenotypic expression of the respective genes. We also make important observations about dominant disorders; these observations include the pattern of de novo variants, the identification of 74 candidate dominant, disease-related genes, and the potential confirmation of 21 previously reported candidates. Finally, we describe the influence of a predominantly autosomal-recessive landscape on the clinical utility of rapid sequencing (Flash Exome). Our cohort's genotypic and phenotypic data represent a unique resource that can contribute to improved variant interpretation through data sharing.

Keywords: autozygome; candidate genes; clinical genomics; dual diagnosis; exome; expanded carrier screening; fetal malformation; first-tier; genomics-first; gonadal mosaicism; hybrid phenotype; knockout; multilocus phenotypes; phenotypic expansion; prenatal.

References

https://pubmed.ncbi.nlm.nih.gov/

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