Unmasking Complex Chromosomal Rearrangement Impacting CHD2 by Genome Sequencing and Optical Genome Mapping in
Robin Wijngaard1, Pinelopi Dragoumi2, Kornelia Neveling1
1Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.
Abstract:
Developmental and epileptic encephalopathy (DEE) is extremely heterogeneous and only 30 to 50% of affected individuals receive a diagnosis upon routine genetic diagnostics. We show that genome sequencing, complemented by optical genome mapping (OGM), resolved an exome-negative case.
Abstract:
We performed trio short-read genome sequencing, karyotyping, OGM, and quantitative real-time PCR.
Abstract:
In a boy with DEE (severe global developmental delay/intellectual disability, early-onset, multiple and concurrent seizures, EEG suggestive of Lennox-Gastaut syndrome, dystonic tetraplegia), routine diagnostic testing (karyotyping, array-CGH, and exome sequencing) failed to yield a diagnosis. Genome sequencing detected a de novo translocation that OGM validated and expanded to a complex chromosomal rearrangement (CCR) involving seven breakpoints in chromosomes 5, 9, 12, and 15. The breakpoint on chromosome 15 affected the 5'UTR promotor region of CHD2. Quantitative real-time PCR on RNA from proband-derived lymphoblast cells showed a 40% reduction of CHD2 expression confirming the pathogenicity of the variant.
Abstract:
Our case highlights that CCR can underly CHD2-related DEE94 and likely underlie other (genetically unsolved) cases. There is not one technique that can detect all genetic variants. We emphasize the advantage of combining genome sequencing with OGM as a complementary second step in unresolved cases to improve the detection and structural characterization of genetic variation, including CCRs.
