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Diagnostic Yield of Whole Genome Sequencing After Nondiagnostic Exome Sequencing or Gene Panel in Developmental and Epileptic Encephalopathies


OBJECTIVE: To assess the benefits and limitations of whole genome sequencing (WGS) compared to exome sequencing (ES) or multigene panel (MGP) in the molecular diagnosis of developmental and epileptic encephalopathies (DEE). METHODS: We performed WGS of 30 comprehensively phenotyped DEE patient trios that were undiagnosed after first-tier testing, including chromosomal microarray and either research ES (n = 15) or diagnostic MGP (n = 15). RESULTS: Eight diagnoses were made in the 15 individuals who received prior ES (53%): 3 individuals had complex structural variants; 5 had ES-detectable variants, which now had additional evidence for pathogenicity. Eleven diagnoses were made in the 15 MGP-negative individuals (68%); the majority (n = 10) involved genes not included in the panel, particularly in individuals with postneonatal onset of seizures and those with more complex presentations including movement disorders, dysmorphic features, or multiorgan involvement. A total of 42% of diagnoses were autosomal recessive or X-chromosome linked. CONCLUSION: WGS was able to improve diagnostic yield over ES primarily through the detection of complex structural variants (n = 3). The higher diagnostic yield was otherwise better attributed to the power of re-analysis rather than inherent advantages of the WGS platform. Additional research is required to assist in the assessment of pathogenicity of novel noncoding and complex structural variants and further improve diagnostic yield for patients with DEE and other neurogenetic disorders.

Type Journal
ISBN 1526-632X (Electronic) 0028-3878 (Linking)
Authors Palmer, E. E.; Sachdev, R.; Macintosh, R.; Melo, U. S.; Mundlos, S.; Righetti, S.; Kandula, T.; Minoche, A. E.; Puttick, C.; Gayevskiy, V.; Hesson, L.; Idrisoglu, S.; Shoubridge, C.; Thai, M. H. N.; Davis, R. L.; Drew, A. P.; Sampaio, H.; Andrews, P. I.; Lawson, J.; Cardamone, M.; Mowat, D.; Colley, A.; Kummerfeld, S.; Dinger, M. E.; Cowley, M. J.; Roscioli, T.; Bye, A.; Kirk, E.
Responsible Garvan Author A/Prof Sarah Kummerfeld
Publisher Name NEUROLOGY
Published Date 2021-03-31
Published Volume 96
Published Issue 13
Published Pages e1770-e1782
Status Published in-print
DOI 10.1212/WNL.0000000000011655
URL link to publisher's version