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Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.
Monies, Dorota; Abouelhoda, Mohammed; Assoum, Mirna; Moghrabi, Nabil; Rafiullah, Rafiullah; Almontashiri, Naif; Alowain, Mohammed; Alzaidan, Hamad; Alsayed, Moeen; Subhani, Shazia; Cupler, Edward; Faden, Maha; Alhashem, Amal; Qari, Alya; Chedrawi, Aziza; Aldhalaan, Hisham; Kurdi, Wesam; Khan, Sameena; Rahbeeni, Zuhair; Alotaibi, Maha; Goljan, Ewa; Elbardisy, Hadeel; ElKalioby, Mohamed; Shah, Zeeshan; Alruwaili, Hibah; Jaafar, Amal; Albar, Ranad; Akilan, Asma; Tayeb, Hamsa; Tahir, Asma; Fawzy, Mohammed; Nasr, Mohammed; Makki, Shaza; Alfaifi, Abdullah; Akleh, Hanna; Yamani, Suad; Bubshait, Dalal; Mahnashi, Mohammed; Basha, Talal; Alsagheir, Afaf; Abu Khaled, Musad; Alsaleem, Khalid; Almugbel, Maisoon; Badawi, Manal; Bashiri, Fahad; Bohlega, Saeed; Sulaiman, Raashida; Tous, Ehab; Ahmed, Syed; Algoufi, Talal.
Afiliação
  • Monies D; 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
  • Abouelhoda M; 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
  • Assoum M; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Moghrabi N; 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
  • Rafiullah R; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Almontashiri N; Clinical Molecular and Biochemical Genetics, Taibah University, Madinah 42353, Saudi Arabia.
  • Alowain M; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Alzaidan H; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Alsayed M; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Subhani S; 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
  • Cupler E; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.
  • Faden M; Genetics and Metabolism, King Saud Medical Complex, Riyadh 12746, Saudi Arabia.
  • Alhashem A; Pediatrics Department, Prince Sultan Military Medical Complex, Riyadh 12233, Saudi Arabia.
  • Qari A; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Chedrawi A; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Aldhalaan H; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Kurdi W; Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Khan S; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Rahbeeni Z; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Alotaibi M; Genetics and Metabolism, King Saud Medical Complex, Riyadh 12746, Saudi Arabia.
  • Goljan E; 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
  • Elbardisy H; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • ElKalioby M; 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.
  • Shah Z; 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
  • Alruwaili H; 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
  • Jaafar A; 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
  • Albar R; Saudi Human Genome Program, King Abdulaziz City for Science and Technology, Riyadh 12354, Saudi Arabia.
  • Akilan A; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Tayeb H; 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
  • Tahir A; 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
  • Fawzy M; 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
  • Nasr M; 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
  • Makki S; Saudi Diagnostic Laboratories, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Alfaifi A; Pediatrics Department, Security Forces Hospital, Riyadh 11481, Saudi Arabia.
  • Akleh H; Academic and Training Affairs, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Yamani S; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Bubshait D; Pediatrics Department, King Fahad Hospital of the University, Al-Khobar 31952, Saudi Arabia.
  • Mahnashi M; Genetics and Medicine, King Fahd Central Hospital, Gizan 82666, Saudi Arabia.
  • Basha T; Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Jeddah 23433, Saudi Arabia.
  • Alsagheir A; Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Abu Khaled M; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Alsaleem K; Pediatrics Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Almugbel M; Obstetrics and Gynecology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Badawi M; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Bashiri F; Department of Pediatrics, College of Medicine and King Khalid University Hospital, King Saud University, Riyadh 11461, Saudi Arabia.
  • Bohlega S; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Sulaiman R; Department of Medical Genetics, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Tous E; Neurosciences Department, King Faisal Specialist Hospital and Research Centre, Riyadh, 11211, Saudi Arabia.
  • Ahmed S; Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
  • Algoufi T; Pediatric Hematology and Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia.
Am J Hum Genet ; 104(6): 1182-1201, 2019 06 06.
Article em En | MEDLINE | ID: mdl-31130284
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Consanguinidade / Predisposição Genética para Doença / Doenças Genéticas Ligadas ao Cromossomo X / Sequenciamento do Exoma / Genes Recessivos / Mutação Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Child / Female / Humans / Male / Pregnancy País/Região como assunto: Asia Idioma: En Revista: Am J Hum Genet Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Consanguinidade / Predisposição Genética para Doença / Doenças Genéticas Ligadas ao Cromossomo X / Sequenciamento do Exoma / Genes Recessivos / Mutação Tipo de estudo: Etiology_studies / Incidence_studies / Observational_studies / Prognostic_studies / Risk_factors_studies Limite: Child / Female / Humans / Male / Pregnancy País/Região como assunto: Asia Idioma: En Revista: Am J Hum Genet Ano de publicação: 2019 Tipo de documento: Article