Publication Details

Title :

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

Journal:

Am J Hum Genet.

Impact Factor:

9.025

Authors:

Monies D1, Abouelhoda M1, Assoum M2, Moghrabi N1, Rafiullah R2, Almontashiri N3, Alowain M4, Alzaidan H4, Alsayed M4, Subhani S1, Cupler E5, Faden M6, Alhashem A7, Qari A4, Chedrawi A8, Aldhalaan H8, Kurdi W9, Khan S8, Rahbeeni Z4, Alotaibi M6, Goljan E1, Elbardisy H2, ElKalioby M10, Shah Z1, Alruwaili H1, Jaafar A1, Albar R11, Akilan A2, Tayeb H1, Tahir A1, Fawzy M1, Nasr M1, Makki S2, Alfaifi A12, Akleh H13, Yamani S8, Bubshait D14, Mahnashi M15, Basha T16, Alsagheir A17, Abu Khaled M8, Alsaleem K17, Almugbel M9, Badawi M8, Bashiri F18, Bohlega S8, Sulaiman R4, Tous E8, Ahmed S19, Algoufi T19, Al-Mousa H20, Alaki E20, Alhumaidi S21, Alghamdi H16, Alghamdi M21, Sahly A17, Nahrir S21, Al-Ahmari A22, Alkuraya H23, Almehaidib A24, Abanemai M24, Alsohaibaini F24, Alsaud B20, Arnaout R20, Abdel-Salam GMH25, Aldhekri H17, AlKhater S26, Alqadi K8, Alsabban E17, Alshareef T27, Awartani K9, Banjar H28, Alsahan N9, Abosoudah I29, Alashwal A30, Aldekhail W24, Alhajjar S31, Al-Mayouf S17, Alsemari A8, Alshuaibi W32, Altala S33, Altalhi A34, Baz S8, Hamad M32, Abalkhail T8, Alenazi B35, Alkaff A9, Almohareb F36, Al Mutairi F37, Alsaleh M19, Alsonbul A38, Alzelaye S39, Bahzad S40, Manee AB17, Jarrad O17, Meriki N41, Albeirouti B42, Alqasmi A21, AlBalwi M43, Makhseed N44, Hassan S32, Salih I45, Salih MA18, Shaheen M46, Sermin S27, Shahrukh S5, Hashmi S46, Shawli A47, Tajuddin A48, Tamim A49, Alnahari A50, Ghemlas I19, Hussein M51, Wali S7, Murad H8, Meyer BF1, Alkuraya FS52.

Affiliations:

1 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

2 Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

3 Clinical Molecular and Biochemical Genetics, Taibah University, Madinah 42353, Saudi Arabia.

4 Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

5 Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.

6 Genetics and Metabolism, King Saud Medical Complex, Riyadh 12746, Saudi Arabia.

7 Pediatrics Department, Prince Sultan Military Medical Complex, Riyadh 12233, Saudi Arabia.

8 Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.

9 Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

10 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

11 Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia.

12 Pediatrics Department, Security Forces Hospital, Riyadh 11481, Saudi Arabia.

13 Academic and Training Affairs, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

14 Pediatrics Department, King Fahad Hospital of the University, Al-Khobar 31952, Saudi Arabia.

15 Genetics and Medicine, King Fahd Central Hospital, Gizan 82666, Saudi Arabia.

16 Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.

17 Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

18 Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh 11461, Saudi Arabia.

19 Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

20 Allergy – Immunology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

21 Pediatrics Department, King Saud Medical City, Riyadh 12746, Saudi Arabia.

22 Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.

23 Vitreoretinal Surgery, Specialized Medical Centre, Riyadh 11564, Saudi Arabia.

24 Gastroenterology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

25 Department of Clinical Genetics, National Research Centre, Cairo 12622, Egypt.

26 Pediatrics Department, King Fahad Hospital of the University, Al-Khobar 31952, Saudi Arabia; Department of Pediatrics, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam 34221, Saudi Arabia.

27 Pediatric Nephrology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

28 Pediatric Pulmonology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

29 Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.

30 Pediatric Endocrine and Metabolism, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

31 Pediatric Infectious Diseases, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

32 Pediatrics Department, King Khalid University Hospital, Riyadh 12372, Saudi Arabia.

33 Pediatrics Department, Armed Forces Hospital, Khamis Mushait 62451, Saudi Arabia.

34 Pediatric Nephrology, King Saud Medical City, Riyadh 12746, Saudi Arabia.

35 Pediatrics Department, Alyamama Hospital, Riyadh 14222, Saudi Arabia.

36 Oncology Center, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

37 King Abdullah International Medical Research Centre, King Saud Bin Abdulaziz University for Health Sciences, Riyadh 11564, Saudi Arabia; Medical Genetic Division, Department of Pediatrics, King Abdulaziz Medical City, Riyadh 14611, Saudi Arabia.

38 Pediatric Rheumatology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

39 Pediatric Endocrine and Diabetes, Al Qunfudah General Hospital, Al Qunfudhah 28821, Saudi Arabia.

40 Kuwait Medical Genetics Center, Kuwait City 65000, Kuwait.

41 Maternal and Fetal Medicine, King Khalid University Hospital, Riyadh 12372, Saudi Arabia.

42 Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.

43 Department of Pathology and Laboratory Medicine, King Saud bin Abdulaziz University for Health Sciences, King Abdullah International Medical Research Center, King Abdulaziz Medical City, Riyadh 11426, Saudi Arabia.

44 Pediatrics Department, Alsoor Clinic, Kuwait City 65000, Kuwait.

45 Hepatic-Pancreatic Surgery, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

46 Hematology and Bone Marrow Transplant, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

47 Department of Pediatrics, King Abdulaziz Medical City, Jeddah 9515, Saudi Arabia.

48 Neurology, King Fahad Hospital, Medina 59046, Saudi Arabia.

49 Pediatrics Neurology, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.

50 Pediatric Department, King Fahad Central Hospital, Gizan, 82666, Saudi Arabia.

51 Nephrology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.

52 Department of Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia; College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia.

Year of Publication:

2019

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.