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Detection of a mosaic CDKL5 deletion and inversion by optical genome mapping ends an exhaustive diagnostic odyssey

Molecular Genetics & Genomic Medicine 2021
Cope H. et al

Background: Currently available structural variant (SV) detection methods do not span the complete spectrum of disease-causing SVs. Optical genome mapping (OGM), an emerging technology with the potential to resolve diagnostic dilemmas, was performed to investigate clinically-relevant SVs in a 4-year-old male with an epileptic encephalopathy of undiagnosed molecular origin.

Methods: OGM was utilized to image long, megabase-size DNA molecules, fluorescently labeled at specific sequence motifs throughout the genome with high sensitivity for detection of SVs greater than 500 bp in size. OGM results were confirmed in a CLIA-certified laboratory via mate-pair sequencing.

Results: OGM identified a mosaic, de novo 90 kb deletion and inversion on the X chromosome disrupting the CDKL5 gene. Detection of the mosaic deletion, which had been previously undetected by chromosomal microarray, an infantile epilepsy panel including exon-level microarray for CDKL5, exome sequencing as well as genome sequencing, resulted in a diagnosis of X-linked dominant early infantile epileptic encephalopathy-2.

Conclusion: OGM affords an effective technology for the detection of SVs, especially those that are mosaic, since these remain difficult to detect with current NGS technologies and with conventional chromosomal microarrays. Further research in undiagnosed populations with OGM is warranted.

Keywords: copy number variants; epilepsy; mosaicism; optical genome mapping; structural variants.


Heidi Cope 1Hayk Barseghyan 2 3 4Surajit Bhattacharya 2Yulong Fu 2Nicole Hoppman 5Cherisse Marcou 5Nicole Walley 1Catherine Rehder 6Kristen Deak 5Anna Alkelai 7Undiagnosed Diseases NetworkEric Vilain 2 3Vandana Shashi 1


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