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Study | Cohort | Timing of WES | Diagnostic yield
|
de Ligt et al., 2012 | 100 patients with severe ID | Trios WES All patients with prior extensive genetic diagnostic work up | Diagnostic yield=16%, 79 de novo mutations in 53 /100, Potential causative variants in 22 novel genes |
Yang et al., 2013 | 250 patients (80% with neurological phenotype) | All patients had undergone prior genetic testing (microarray, metabolic screening and specific gene sequencing) | Diagnostic yield – 62/250 (25%), autosomal dominant =33, autosomal recessive =16, X-linked disease=9, Four probands with 2 non-overlapping diagnoses |
Yang et al., 2014 | 2000 patients, 87.8% with neurological phenotype | All patients had undergone some prior diagnostic workup including specific genetic tests | Diagnosis in 504 (25.2%), novel variants in 58%, 6 patients with large deletions, 23 had mutations at 2 different loci |
Willemsen et al., 2014 | 253 individuals from 234 Dutch families with unexplained ID | 2 phases- diagnostic (specific genetic test, microarray, metabolic screen) and research phase (NGS in 30% of undiagnosed patients in phase I) | Phase I - diagnosis in 43 (18.4%). Phase II - pertinent/plausible diagnosis in 24 /58 (41.4%) in NGS cohort. Total diagnostic potential combining both phases = 59.8%. |
Sawyer et al., 2015 | >500 children from 362 families with rare genetic diseases, mainly neurodevelopmental and dysmorphism disorders | All had already received standard of care genetics evaluation | Mutations in known disease genes for 105 of 362 families studied (29%), Neurodevelopmental phenotype- yield was 31.6% |
Riyazuddin et al., 2016 | 121 large consanguineous Pakistani families with ID | All patients had clinical +/- neuroimaging evaluation. No prior genetic test was done | Total yield - 68 families (56.2%) Novel genes - 30 families |
Anazi et al., 2016 | 337 ID subjects, high prevalence of consanguinity | Molecular karyotyping, multigene panels, WES were used as first-tier tests, compared with standard clinical evaluation done in parallel | Standard clinical evaluation suggested a diagnosis in 16% (54/337), only 70% of these (38/54) were confirmed. Genomic approach revealed a likely diagnosis in 58% (n = 196). These included CNVs in 14% (n = 54, 15% are novel), and point mutations in remaining 43% |
In addition to the high cost, the vast amount of data, which is a challenge for analysis and storage, is a major problem being faced. The advantage of WES is that the need of a clinical differential diagnosis is not a must and WES can identify the etiology in a case with a nonspecific or a subtle phenotype. The same advantage of covering all the genes poses challenges for analysis analysis as in some cases more than one pathogenic sequence variant may be identified or many variations of unknown significance are identified. These issues will gradually get minimized or resolved as more and more parts of the genome get annotated and databases of pathogenic and non-pathogenic variations become more comprehensive. One of the reservations which many physicians have in implementing this approach is the high cost of WES. A recent study comparing the cost of WES with conventional diagnostic approaches in a cohort of individuals with intellectual disability found that the traditional diagnostic trajectory cost was $16,409 per patient while the trio-WES cost was $3,972 only. They concluded that WES resulted in average cost savings of $3,547 for genetic and metabolic investigations in diagnosed patients and $1,727 for genetic investigations in undiagnosed patients (Monroe et al., 2016). Another concern is the inability of WES to detect copy number variations (CNVs), which cause a large proportion of intellectual disability. But in recent years, there have been many publications evaluating the utility of WES in detecting CNVs by various algorithms. These studies have reported a fair rate for detection of CNVs, 59 to 89% with the sensitivity increasing with CNVs >200kb in size (Tetreault et al., 2015; Miyatake et al., 2016). In the current situation, WES as a first-tier test in neurodevelopmental disorders appears to be an attractive option especially in families with consanguinity, multiple affected members, clinical features suggestive of a monogenic phenotype with no obvious cause and after the cytogenetic microarray is normal. More and more experience and data will provide answers to today’s challenges of technical issues (like coverage), accurate interpretation of the huge data generated, incidental findings, functional validation of novel variants, and need for more robust algorithms for CNV detection.
To get the estimate of clinical utility of WES in the diagnosis of genetic phenotypes, a lot of work is needed and has already been started. The important one to be mentioned here is the Clinical Sequencing Exploratory Research (CSER) consortium which includes eighteen projects which not only are exploring clinical utility and clinical validity of clinical genome and exome sequencing, but is also looking at the ethical, social and legal implications via multidisciplinary approaches (Green et al, 2016). Similar efforts being done are ‘Genome Clinic Task Force’ (Fokstuen et al., 2016) and the ‘SickKids Genome Clinic’ (Bowdin et al., 2016). The analysis of these big studies will provide answers to the questions about appropriate use and timing of the WES-based diagnosis which is powerful but costly and has some issues which need to be sorted.
Diagnosis of genetic disorders is an arduous and challenging task. The armamentarium of advanced genetic testing is improving the etiological diagnosis and thus helping the families. Cytogenetic microarray is considered the first tier test for evaluation of a child with a neurodevelopmental disorder. However, it should be noted that detailed clinical evaluation, appropriate imaging and biochemical investigations constitute the first step in the direction of diagnosis. As is the experience of clinical geneticists, a study of different clinical genetics centres has shown that in patients with dysmorphism, the diagnosis is achieved in the first visit in 30 to 60% of cases (Douzgou et al., 2016). However, WES offers the hope of diagnosis in many cases where there was none. In the future, whole genome sequencing (WGS) is expected to eventually replace WES and even cytogenetic microarray, as it is the single genetic test which has the potential to detect the whole spectrum of genetic aberrations ranging from single nucleotide variations to complex genomic rearrangements. However, at present and during the next few years, exome sequencing will fill the niche of being the most versatile, relatively inexpensive and hence popular application of NGS in the clinic (Tetreault et al., 2015). Its application early-on in the evaluation process of patients with non-specific intellectual disability will have a significant impact in ending the “diagnostic odyssey”.
1. Anazi S, et al. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Mol Psychiatry 2016. doi: 10.1038/mp.2016.113. [Epub ahead of print]
2. Bowdin SC, et al. The Sick Kids Genome Clinic: developing and evaluating a pediatric model for individualized genomic medicine. Clin Genet 2016; 89:10-19.
3. Douzgou S, et al. Dysmorphology services: a snapshot of current practices and a vision for the future. Clin Genet 2016; 89: 27-33.
4. Green RC, et al. CSER Consortium. Clinical Sequencing Exploratory Research Consortium: Accelerating Evidence-Based Practice of Genomic Medicine. Am J Hum Genet 2016; 98: 1051-1066.
5. Fokstuen S, et al. Experience of a multidisciplinary task force with exome sequencing for Mendelian disorders. Hum Genomics 2016; 10: 24.
6. de Ligt J, et al. Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 2012; 367: 1921-1929.
7. Michelson D J, et al. Evidence Report: Genetic and metabolic testing on children with global developmental delay: Report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology 2011; 77: 1629.
8. Miyatake S, et al. Detecting copy-number variations in whole-exome sequencing data using the eXome Hidden Markov Model: an ‘exome-first’ approach. J Hum Genet 2015; 60:175-182.
9. Moeschler JB & Shevell M. Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics 2014; 134: e903-918.
10. Monroe GR, et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med 2016. doi: 10.1038/gim.2015.200. [Epub ahead of print].
11. Riazuddin S, et al. Exome sequencing of Pakistani consanguineous families identifies 30 novel candidate genes for recessive intellectual disability. Mol Psychiatry 2016.doi: 10.1038/mp.2016.109. [Epub ahead of print].
12. Retterer K, et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016; 18: 696-704.
13. Sawyer SL, et al. Utility of whole-exome sequencing for those near the end of the diagnostic odyssey: time to address gaps in care. Clin Genet 2016; 89: 275-284.
14. Shaheen R, et al. Accelerating matchmaking of novel dysmorphology syndromes through clinical and genomic characterization of a large cohort. Genet Med 2016; 18: 686-695.
15. Tetreault M, et al. Whole-exome sequencing as a diagnostic tool: current challenges and future opportunities. Expert Rev Mol Diagn 2015; 15: 749-760.
16. Thevenon J, et al. Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test. Clin Genet 2016: 89: 700-707.
17. Willemsen MH, Kleefstra T. Making headway with genetic diagnostics of intellectual disabilities. Clin Genet 2014; 85: 101-110.
18. Yang Y, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013; 369: 1502-1511.
19. Yang Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014; 312: 1870-1879.
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