Whole-Genome Sequencing Diagnoses Early Infantile Epileptic Encephalopathy

Early infantile epileptic encephalopathy (EIEE) is a rare epilepsy syndrome that causes intractable seizures with multiple seizure types and presents in the first months of life. While the prevalence of EIEE is unclear, and only affects a subset of all infants with seizures, infants with EIEE have serious medical complications.

EIEE patients typically exhibit developmental delay, profound intellectual impairment, and progress to severe psychomotor impairment and early death. Structural brain malformations, birth injury, and inborn errors of metabolism can cause EIEE, but once these causes are accounted for most remaining cases of EIEE are presumed to have a genetic basis.

Scientists at the University of Utah School of Medicine (Salt Lake City, UT, USA) combined deep whole-genome sequencing and a new reference-free de novo variant calling algorithm they developed and applied it to a cohort of 14 patients for whom previous testing led to no diagnosis. The team prioritized the variants they found based on whether they were missense, frameshift, or nonsense variants that fell in known EIEE genes, candidate EIEE genes, or other regions using the GEMINI framework. The team used the Illumina HiSeq X platform to sequence the 14 individuals they recruited into their study, as well both parents of each child, to an average 65X coverage.

The investigators found that for nine patients, they uncovered single, de novo variants in which they had high confidence in pathogenicity. For seven, they found de novo missense mutations affecting ion channel genes like SCNA1, SCN2A, and KCNQ2 that have known links to EIEE. In the two others, they found missense mutations affecting the EEF1A2 and PIGA genes. In two additional patients, they uncovered de novo missense of putative loss-of-function mutations in the protein-coding region of genes that hadn't before been associated with EIEE: DEAF1 and CAMK2G.

The authors concluded that whole-genome sequencing offers a number of advantages for diagnosing monogenic diseases like EIEE. One such advantage, they said is cost. Even though the cost of sequencing remains high, they noted the participants in their study had undergone, in some cases, years of diagnostics tests, each had undergone a minimum of 24 diagnostic tests, costing an average USD 30,866. Whole-genome sequencing, they concluded, could save both time and money. The study was published on August 13, 2018, in the journal npj Genomic Medicine.

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University of Utah School of Medicine