Use of whole exome and genome sequencing in the identification of genetic causes of primary immunodeficiencies

aDivision of Immunology, Boston Children's Hospital bDepartment of Pediatrics, Harvard Medical School cDepartment of Molecular Biology, Massachusetts General Hospital dDepartment of Genetics, Harvard Medical School, Boston, Massachusetts, USA.
Current Opinion in Allergy and Clinical Immunology (Impact Factor: 3.57). 12/2012; 12(6):623-8. DOI: 10.1097/ACI.0b013e3283588ca6
Source: PubMed


This review discusses the strengths and challenges of using whole genome sequencing (WGS)/whole exome sequencing (WES) for identifying novel genetic causes of primary immunodeficiencies.
WGS permits comprehensive sequencing of introns and exons, whereas WES allows deeper sequencing of exonic regions at a lower cost. Due to the large number of genetic variants found in each genome, it is necessary to use filtering approaches to distinguish deleterious from benign variants. WES has been used successfully to identify novel genetic causes of primary immunodeficiency. Complex structural variations and non-Mendelian disorders remain challenges for WGS/WES.
WGS/WES is a powerful screening tool with great potential to identify genetic causes of primary immunodeficiencies for research and clinical applications. To use WGS/WES effectively, it is necessary to understand how to filter the sequencing data and to realize its limitations as well as its strengths.

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    • "Targeted exome sequencing (TES) has been shown to be more efficient than traditional sequencing in the discovery of novel disorder-related genes or mutations in large genomic regions [6]–[9]. Therefore, TES be advantageous in comprehensively screening heterozygous carriers for a panel of known BBS genes. "
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    ABSTRACT: Bardet-Biedl syndrome (BBS) is an autosomal recessive disorder with significant genetic heterogeneity. BBS is linked to mutations in 17 genes, which contain more than 200 coding exons. Currently, BBS is diagnosed by direct DNA sequencing for mutations in these genes, which because of the large genomic screening region is both time-consuming and expensive. In order to develop a practical method for the clinic diagnosis of BBS, we have developed a high-throughput targeted exome sequencing (TES) for genetic diagnosis. Five typical BBS patients were recruited and screened for mutations in a total of 144 known genes responsible for inherited retinal diseases, a hallmark symptom of BBS. The genomic DNA of these patients and their families were subjected to high-throughput DNA re-sequencing. Deep bioinformatics analysis was carried out to filter the massive sequencing data, which were further confirmed through co-segregation analysis. TES successfully revealed mutations in BBS genes in each patient and family member. Six pathological mutations, including five novel mutations, were revealed in the genes BBS2, MKKS, ARL6, MKS1. This study represents the first report of targeted exome sequencing in BBS patients and demonstrates that high-throughput TES is an accurate and rapid method for the genetic diagnosis of BBS.
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    ABSTRACT: The recent development of human exome sequencing technology has revealed that our immune system is riddled with more genetic defects than anyone imagined. As a legacy of the recent human population explosion, we each inherit hundreds of rare mutations that alter the sequence of proteins. This mutation load is ten times higher than that induced by experimental treatment of mice by ethylnitrosourea; a high fraction of which has substantial effects on immune function. This mutation burden is likely to be a major factor in the incidence of many human immune disorders, but understanding this at the level of individual patients will require new bioinformatics and experimental strategies to assess the impact of individual and combined mutations on immune response pathways.
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