To evaluate the performance of proband-only medical exome sequencing (POMES) as a cost-effective first-tier diagnostic test for pediatric patients with unselected conditions.
A total of 1,323 patients were tested by POMES, which targeted 2,742 known disease-causing genes. Clinical relevant variants were Sanger-confirmed in probands and parents. We assessed the diagnostic validity and clinical utility of POMES by means of a survey questionnaire.
POMES, ordered by 136 physicians, identified 512 pathogenic or likely pathogenic variants associated with over 200 conditions. The overall diagnostic rate was 28.8%, ranging from 10% in neonatal intensive care unit patients to over 35% in pediatric intensive care unit patients. The test results had an impact on the management of the 45.1% of patients for whom there were positive findings. The average turnaround time was 57 days; the cost was $360/case.
We adopted a relatively efficient and cost-effective approach in China for the molecular diagnosis of pediatric patients with suspected genetic conditions. While training for clinical geneticists and other specialists is lagging behind in China POMES is serving as a diagnostic equalizer for patients who do not normally receive extensive clinical evaluation and clinical diagnosis prior to testing. This Chinese experience should be applicable to other developing countries that are lacking clinical, financial, and personnel resources.
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Lee H, Deignan JL, Dorrani N et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 2014;312;1880–7.
Yang Y, Muzny DM, Reid JG et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369;1502–11.
Yang Y, Muzny DM, Xia F et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 2014;312;1870–9.
Retterer K, Juusola J, Cho MT et al. Clinical application of whole-exome sequencing across clinical indications. Genet Med 2016;18;696–704.
Farwell KD, Shahmirzadi L, El-Khechen D et al. Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med 2015;17;578–86.
Stark Z, Tan TY, Chong B et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med 2016;18;1090–1096.
Vissers LE, van Nimwegen KJ, Schieving JH et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med 2017;19;1055–1063.
Nguyen MT, Charlebois K. The clinical utility of whole-exome sequencing in the context of rare diseases - the changing tides of medical practice. Clin Genet 2015;88;313–9.
Monroe GR, Frederix GW, Savelberg SM et al. Effectiveness of whole-exome sequencing and costs of the traditional diagnostic trajectory in children with intellectual disability. Genet Med 2016;18;949–56.
Stark Z, Schofield D, Alam K et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med 2017;19;867–874.
Richards S, Aziz N, Bale S et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17;405–424.
Hu X. All 512 pathogenic or likely pathogenic variants detected in 410 patients. https://figshare.com/articles/All_512_pathogenic_or_likely_pathogenic_variants_detected_in_410_patients/5334034. 22 August 2017.
Chen Y, Lu J, Pan H et al. Association between genetic variation of CACNA1H and childhood absence epilepsy. Ann Neurol 2003;54;239–243.
Boycott KM, Rath A, Chong JX et al. International Cooperation to Enable the Diagnosis of All Rare Genetic Diseases. Am J Hum Genet 2017;100;695–705.
Saudi Mendeliome Group. Comprehensive gene panels provide advantages over clinical exome sequencing for Mendelian diseases. Genome Biol 2015;16;134.
This work was supported by the Natural Science Foundation of China (grants 81371903 and 81472051), the Shanghai Science and Technology Commission for major issues (grant 11dz1950300), a project of the Shanghai Municipal Science and Technology Commission (grant 15410722800), a project of the Shanghai Municipal Education Commission–Gaofeng Clinical Medicine (grant 20152529), the “Eastern Scholar” Fund, and the China Scholarship Council. The authors wish to thank Dr. James Gusella and Ms. Pamela Gerrol for revising the manuscript.
Conflict of Interest
The authors declare no conflict of interest.
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