Dataset Information

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

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2,200 previously unpublished Saudi families as a first-tier test.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.

SUBMITTER: Monies D

PROVIDER: S-EPMC6562004 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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

Monies Dorota D Abouelhoda Mohammed M Assoum Mirna M Moghrabi Nabil N Rafiullah Rafiullah R Almontashiri Naif N Alowain Mohammed M Alzaidan Hamad H Alsayed Moeen M Subhani Shazia S Cupler Edward E Faden Maha M Alhashem Amal A Qari Alya A Chedrawi Aziza A Aldhalaan Hisham H Kurdi Wesam W Khan Sameena S Rahbeeni Zuhair Z Alotaibi Maha M Goljan Ewa E Elbardisy Hadeel H ElKalioby Mohamed M Shah Zeeshan Z Alruwaili Hibah H Jaafar Amal A Albar Ranad R Akilan Asma A Tayeb Hamsa H Tahir Asma A Fawzy Mohammed M Nasr Mohammed M Makki Shaza S Alfaifi Abdullah A Akleh Hanna H Yamani Suad S Bubshait Dalal D Mahnashi Mohammed M Basha Talal T Alsagheir Afaf A Abu Khaled Musad M Alsaleem Khalid K Almugbel Maisoon M Badawi Manal M Bashiri Fahad F Bohlega Saeed S Sulaiman Raashida R Tous Ehab E Ahmed Syed S Algoufi Talal T Al-Mousa Hamoud H Alaki Emadia E Alhumaidi Susan S Alghamdi Hadeel H Alghamdi Malak M Sahly Ahmed A Nahrir Shapar S Al-Ahmari Ali A Alkuraya Hisham H Almehaidib Ali A Abanemai Mohammed M Alsohaibaini Fahad F Alsaud Bandar B Arnaout Rand R Abdel-Salam Ghada M H GMH Aldhekri Hasan H AlKhater Suzan S Alqadi Khalid K Alsabban Essam E Alshareef Turki T Awartani Khalid K Banjar Hanaa H Alsahan Nada N Abosoudah Ibraheem I Alashwal Abdullah A Aldekhail Wajeeh W Alhajjar Sami S Al-Mayouf Sulaiman S Alsemari Abdulaziz A Alshuaibi Walaa W Altala Saeed S Altalhi Abdulhadi A Baz Salah S Hamad Muddathir M Abalkhail Tariq T Alenazi Badi B Alkaff Alya A Almohareb Fahad F Al Mutairi Fuad F Alsaleh Mona M Alsonbul Abdullah A Alzelaye Somaya S Bahzad Shakir S Manee Abdulaziz Bin AB Jarrad Ola O Meriki Neama N Albeirouti Bassem B Alqasmi Amal A AlBalwi Mohammed M Makhseed Nawal N Hassan Saeed S Salih Isam I Salih Mustafa A MA Shaheen Marwan M Sermin Saadeh S Shahrukh Shamsad S Hashmi Shahrukh S Shawli Ayman A Tajuddin Ameen A Tamim Abdullah A Alnahari Ahmed A Ghemlas Ibrahim I Hussein Maged M Wali Sami S Murad Hatem H Meyer Brian F BF Alkuraya Fowzan S FS

American journal of human genetics 20190523 6

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 associa ...[more]

PMID: 31130284

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Project description:BackgroundGiven the rarity of most single-gene Mendelian disorders, concerted efforts of data exchange between clinical and scientific communities are critical to optimize molecular diagnosis and novel disease gene discovery.MethodsWe designed and implemented protocols for the study of cases for which a plausible molecular diagnosis was not achieved in a clinical genomics diagnostic laboratory (i.e. unsolved clinical exomes). Such cases were recruited to a research laboratory for further analyses, in order to potentially: (1) accelerate novel disease gene discovery; (2) increase the molecular diagnostic yield of whole exome sequencing (WES); and (3) gain insight into the genetic mechanisms of disease. Pilot project data included 74 families, consisting mostly of parent-offspring trios. Analyses performed on a research basis employed both WES from additional family members and complementary bioinformatics approaches and protocols.ResultsAnalysis of all possible modes of Mendelian inheritance, focusing on both single nucleotide variants (SNV) and copy number variant (CNV) alleles, yielded a likely contributory variant in 36% (27/74) of cases. If one includes candidate genes with variants identified within a single family, a potential contributory variant was identified in a total of ~51% (38/74) of cases enrolled in this pilot study. The molecular diagnosis was achieved in 30/63 trios (47.6%). Besides this, the analysis workflow yielded evidence for pathogenic variants in disease-associated genes in 4/6 singleton cases (66.6%), 1/1 multiplex family involving three affected siblings, and 3/4 (75%) quartet families. Both the analytical pipeline and the collaborative efforts between the diagnostic and research laboratories provided insights that allowed recent disease gene discoveries (PURA, TANGO2, EMC1, GNB5, ATAD3A, and MIPEP) and increased the number of novel genes, defined in this study as genes identified in more than one family (DHX30 and EBF3).ConclusionAn efficient genomics pipeline in which clinical sequencing in a diagnostic laboratory is followed by the detailed reanalysis of unsolved cases in a research environment, supplemented with WES data from additional family members, and subject to adjuvant bioinformatics analyses including relaxed variant filtering parameters in informatics pipelines, can enhance the molecular diagnostic yield and provide mechanistic insights into Mendelian disorders. Implementing these approaches requires collaborative clinical molecular diagnostic and research efforts.

Dataset Information

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

Publications

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

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