Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

Betsy E.P. Ostrander; Russell J. Butterfield; Brent S. Pedersen; Andrew J. Farrell; Ryan M. Layer; Alistair Ward; Chase Miller; Tonya DiSera; Francis M. Filloux; Meghan S. Candee; Tara Newcomb; Joshua L. Bonkowsky; Gabor T. Marth; Aaron R. Quinlan

doi:10.1038/s41525-018-0061-8

Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

Betsy E.P. Ostrander, Russell J. Butterfield, Brent S. Pedersen, Andrew J. Farrell, Ryan M. Layer, Alistair Ward, Chase Miller, Tonya DiSera, Francis M. Filloux, Meghan S. Candee, Tara Newcomb, Joshua L. Bonkowsky, Gabor T. Marth, Aaron R. Quinlan

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Abstract

Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.

Original language	English
Article number	22
Journal	npj Genomic Medicine
Volume	3
Issue number	1
DOIs	https://doi.org/10.1038/s41525-018-0061-8
State	Published - Dec 1 2018
Externally published	Yes

Funding

J.L.B. was supported by NIH grant DP2 MH100008. A.R.Q. was supported by the US National Institutes of Health National grants NIH R01HG006693 and NIH R01HG009141 (National Human Genome Research Institute), NIH R01GM124355 (National Institute of General Medical Sciences), and U24CA209999 (National Cancer Institute). G.T.M. was supported by the US National Institutes of Health (grants U01HG006513 and R01HG009712 by NHGRI, and supplement 3UL1TR001067-04S2 by NCATS). The authors gratefully acknowledge the Utah Genome Project and the Chan Soon-Shiong Family Foundation for providing the funds for sequencing the study samples.

Funders	Funder number
Chan Soon-Shiong Family Foundation
US National Institutes of Health
Utah Genome Project
National Institutes of Health	R01HG009141, U01HG006513, R01HG009712, DP2 MH100008
National Human Genome Research Institute	R01HG006693, 3UL1TR001067-04S2
National Cancer Institute
National Institute of General Medical Sciences	R01GM124355, U24CA209999
National Center for Advancing Translational Sciences

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Ostrander, B. E. P., Butterfield, R. J., Pedersen, B. S., Farrell, A. J., Layer, R. M., Ward, A., Miller, C., DiSera, T., Filloux, F. M., Candee, M. S., Newcomb, T., Bonkowsky, J. L., Marth, G. T., & Quinlan, A. R. (2018). Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy. npj Genomic Medicine, 3(1), Article 22. https://doi.org/10.1038/s41525-018-0061-8

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title = "Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy",

abstract = "Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.",

author = "Ostrander, {Betsy E.P.} and Butterfield, {Russell J.} and Pedersen, {Brent S.} and Farrell, {Andrew J.} and Layer, {Ryan M.} and Alistair Ward and Chase Miller and Tonya DiSera and Filloux, {Francis M.} and Candee, {Meghan S.} and Tara Newcomb and Bonkowsky, {Joshua L.} and Marth, {Gabor T.} and Quinlan, {Aaron R.}",

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Ostrander, BEP, Butterfield, RJ, Pedersen, BS, Farrell, AJ, Layer, RM, Ward, A, Miller, C, DiSera, T, Filloux, FM, Candee, MS, Newcomb, T, Bonkowsky, JL, Marth, GT & Quinlan, AR 2018, 'Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy', npj Genomic Medicine, vol. 3, no. 1, 22. https://doi.org/10.1038/s41525-018-0061-8

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AU - Ostrander, Betsy E.P.

AU - Butterfield, Russell J.

AU - Pedersen, Brent S.

AU - Farrell, Andrew J.

AU - Layer, Ryan M.

AU - Ward, Alistair

AU - Miller, Chase

AU - DiSera, Tonya

AU - Filloux, Francis M.

AU - Candee, Meghan S.

AU - Newcomb, Tara

AU - Bonkowsky, Joshua L.

AU - Marth, Gabor T.

AU - Quinlan, Aaron R.

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N2 - Early infantile epileptic encephalopathy (EIEE) is a devastating epilepsy syndrome with onset in the first months of life. Although mutations in more than 50 different genes are known to cause EIEE, current diagnostic yields with gene panel tests or whole-exome sequencing are below 60%. We applied whole-genome analysis (WGA) consisting of whole-genome sequencing and comprehensive variant discovery approaches to a cohort of 14 EIEE subjects for whom prior genetic tests had not yielded a diagnosis. We identified both de novo point and INDEL mutations and de novo structural rearrangements in known EIEE genes, as well as mutations in genes not previously associated with EIEE. The detection of a pathogenic or likely pathogenic mutation in all 14 subjects demonstrates the utility of WGA to reduce the time and costs of clinical diagnosis of EIEE. While exome sequencing may have detected 12 of the 14 causal mutations, 3 of the 12 patients received non-diagnostic exome panel tests prior to genome sequencing. Thus, given the continued decline of sequencing costs, our results support the use of WGA with comprehensive variant discovery as an efficient strategy for the clinical diagnosis of EIEE and other genetic conditions.

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Whole-genome analysis for effective clinical diagnosis and gene discovery in early infantile epileptic encephalopathy

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