Targeted gene sequencing in 6994 individuals with neurodevelopmental disorder with epilepsy

Abstract

Purpose

We aimed to gain insight into frequencies of genetic variants in genes implicated in neurodevelopmental disorder with epilepsy (NDD+E) by investigating large cohorts of patients in a diagnostic setting.

Methods

We analyzed variants in NDD+E using epilepsy gene panel sequencing performed between 2013 and 2017 by two large diagnostic companies. We compared variant frequencies in 6994 panels with another 8588 recently published panels as well as exome-wide de novo variants in 1942 individuals with NDD+E and 10,937 controls.

Results

Genes with highest frequencies of ultrarare variants in NDD+E comprised SCN1A, KCNQ2, SCN2A, CDKL5, SCN8A, and STXBP1, concordant with the two other epilepsy cohorts we investigated. In only 46% of the analyzed 262 dominant and X-linked panel genes ultrarare variants in patients were reported. Among genes with contradictory evidence of association with epilepsy, CACNB4, CLCN2, EFHC1, GABRD, MAGI2, and SRPX2 showed equal frequencies in cases and controls.

Conclusion

We show that improvement of panel design increased diagnostic yield over time, but panels still display genes with low or no diagnostic yield. With our data, we hope to improve current diagnostic NDD+E panel design and provide a resource of ultrarare variants in individuals with NDD+E to the community.

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Code availability

All statistical analyses were done with the R programming language (www.r-project.org). The code is available upon request.

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Acknowledgements

We thank the team of the Institute of Human Genetics of the University of Leipzig as well as the Analytic and Translational Genetics Unit, Boston, for helpful discussions. H.O.H. was supported by stipends from the Federal Ministry of Education and Research (BMBF), Germany, FKZ: 01EO1501 and the German Research Foundation (DFG): HE7987/1–1 and HE7987/1–2. Y.G.W. was supported by DFG grants WE4896/3–1 and WE4896/4–1.

Author information

Correspondence to Henrike O. Heyne MD or Johannes R. Lemke MD.

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Disclosure

The data presented here come from two commercial companies. C.M.S., V.T. and D.R.S. have been employees of Courtagen. S.B. is an owner of CeGaT, F.B. is an employee of CeGaT. The other authors declare no conflicts of interest.

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Keywords

  • epilepsy
  • gene panel design
  • Mendelian genetics
  • clinical genetics, neurodevelopmental disorder