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. 2018 Aug 13;3:22.
doi: 10.1038/s41525-018-0061-8. eCollection 2018.

Whole-genome Analysis for Effective Clinical Diagnosis and Gene Discovery in Early Infantile Epileptic Encephalopathy

Free PMC article

Whole-genome Analysis for Effective Clinical Diagnosis and Gene Discovery in Early Infantile Epileptic Encephalopathy

Betsy E P Ostrander et al. NPJ Genom Med. .
Free PMC article


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.

Conflict of interest statement

The authors declare no competing interests.


Fig. 1
Fig. 1
a A 63 kb de novo tandem duplication in CDKL5 duplicates exons 5 through 15 (for Ensembl canonical transcript ENST00000379989) in subject 7. b Targeted cDNA sequencing confirms the predicted frameshift and stop gain mutation caused by the de novo tandem duplication
Fig. 2
Fig. 2
An inverted, reciprocal translocation between chromosomes X and 2. a The inverted translocation in subject 2 results in DNA exchange between the X chromosome and chromosome 2. The chromosome 2 break occurred in the p arm at position 59,405,748, leaving minor (24%) and major (76%) portions, and the chromosome X break occurred at the extreme q arm at position 151,118,513 leaving a minor (3%) and major (97%) portions. As a result, GABRE, GABRA3, and MECP2 are translocated from the X chromosome to chromosome 2. b A de novo mutation in subject 2 is also observed that is intronic to multiple isoforms (e.g., ENST00000303391) of MECP2 and upstream of other isoforms (e.g., ENST00000415944) of MECP2. The mutation lies within the observed binding site of multiple transcription factors, including Pol II
Fig. 3
Fig. 3
Gene.iobio screenshot of the diagnostic de novo variant in subject #3, detected in the SCN8A gene. a Candidate gene panel, in this example displaying the phenotype-driven EIEE candidate gene list generated by the integrated Phenolyzer tool. b Gene analysis panel showing the status and results of the analysis on all candidate genes. Analyzed genes are sorted by the most likely causative variant, resulting in the SCN8A at the top of the list. c Variant ranking panel, displaying the single, non-synonymous de novo mutation in gene SCN8A (indicated by the red arrow). d Variant and sequence coverage track for the proband. Based on the filters selected in the filtering panel (not shown), only de novo mutations in the gene are shown, in this example a single variant marked by the red arrow. e Variant and sequence coverage track in the proband’s mother, showing all variants, inherited and de novo, in this sample. f Variant and sequence coverage track in the proband’s father, showing all variants, inherited and de novo, in this sample

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