Genotype–phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing



As clinical exome sequencing (CES) becomes more common, understanding which patients are most likely to benefit and in what manner is critical for the general pediatrics community to appreciate.


Five hundred and twenty-three patients referred to the Pediatric Genetics clinic at Michigan Medicine were systematically phenotyped by the presence or absence of abnormalities for 13 body/organ systems by a Clinical Genetics team. All patients then underwent CES.


Overall, 30% of patients who underwent CES had an identified pathogenic mutation. The most common phenotypes were developmental delay (83%), neuromuscular system abnormalities (81%), and multiple congenital anomalies (42%). In all, 67% of patients had a variant of uncertain significance (VUS) or gene of uncertain significance (GUS); 23% had no variants reported. There was a significant difference in the average number of body systems affected among these groups (pathogenic 5.89, VUS 6.0, GUS 6.12, and no variant 4.6; P < 0.00001). Representative cases highlight four ways in which CES is changing clinical pediatric practice.


Patients with identified variants are enriched for multiple organ system involvement. Furthermore, our phenotyping provides broad insights into which patients are most likely to benefit from genetics referral and CES and how those results can help guide clinical practice more generally.

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We thank the patients and their families, as well as the clerical staff in the Genetics Clinic, and the research coordinators of the University of Michigan Children’s Clinical Trial Support Unit: Chaandini Jayachandran, MS, CCRP; Alyssa Paul, MS, CCRC; Jonathon Wilbur, BS; Ciara Ivantics, MS; Amy Hurst, BS; Andy Brosius, BS. All phases of this study were supported by The University of Michigan, Department of Pediatrics and the Alfred A. Taubman Medical Research Institute. D.M.M. is also funded by the National Institutes of Health (NIH) DC R01-014456 and by the Donita B. Sullivan, MD, Research Professorship in Pediatrics. J.W.I. is supported by the Morton S. and Henrietta K. Sellner Professorship in Human Genetics.

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D.M.M., M.N.Z., J.W.I., and J.A.B. conceptualized and designed the study, coordinated and supervised data collection and data analysis, drafted the initial manuscript, and reviewed and revised the manuscript. A.A., M.C.H., C.E.K., and S.C.Q. directly evaluated patients, coordinated and supervised data collection, and critically reviewed the manuscript for intellectual content. N.W., R.F., M.G., J.E.J., K.N.L., T.B.M., J.D.O., B.C.O., L.S., L.T., S.B., and N.L.H. collected data and reviewed and revised the manuscript for intellectual content. All authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.

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Correspondence to Donna M. Martin.

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Ziats, M.N., Ahmad, A., Bernat, J.A. et al. Genotype–phenotype analysis of 523 patients by genetics evaluation and clinical exome sequencing. Pediatr Res 87, 735–739 (2020).

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