Pediatric Academic Societies Meeting 2019
Baltimore Convention Center, Baltimore, US
April 27, 2019
Poster presentation

Multifocal and multifaceted genomic crisis leading to highly complex chromosomal rearrangements in a boy with congenital disorders
Atsushi Hattori1, Kohji Okamura1, Yumiko Terada1, Rika Tanaka2, Yuko Katoh-Fukui1, Yoichi Matsubara1, Keiko Matsubara1, Masayo Kagami1, Reiko Horikawa1, and Maki Fukami1
1NCCHD, Japan, 2Aiiku Hosp., Japan
Several mechanisms have been reported to produce genomic variations in the germline. Among these, chromothripsis and chromoanasynthesis create structural variations through catastrophic chromosomal shattering, whereas a "copy number variant mutator phenotype" generates independent structural variations on multiple chromosomes. Importantly, these mechanisms modify the genome through one event, i.e., either non-homologous end joining after DNA double strand breaks or a replication-based error. Here, we report a case with a unique combination of five independent genomic rearrangements which cannot be ascribed to known mechanisms. To elucidate the underlying mechanism of extremely complex germline rearrangements in a patient with congenital disorders. The patient was a one-year-old boy presented with transient neonatal diabetes mellitus, growth retardation, developmental retardation, and multiple congenital anomalies. To clarify the molecular basis of this phenotype, we performed DNA methylation analysis, microarray-based comparative genomic hybridization (aCGH), and linked-read whole genome sequencing. DNA methylation analysis and aCGH revealed that diabetes was caused by duplication of 6q24 region encompassing PLAGL1 on the paternally-derived chromosome. Furthermore, we identified five independent genomic rearrangements on five chromosomes. The multifocal rearrangements consisted of deletions, duplications, and inversions, as well as catastrophic rearrangements due to chromosome pulverization. All five genomic rearrangements appeared to have occurred de novo on paternally derived chromosomes. Duplications were found to have occurred before meiotic recombination. Most deletions, inversions, and catastrophic rearrangements were ascribable to non-homologous end joining, while duplications were presumably caused by a replication-based error. The present case suggests a novel mechanism leading to germline genomic rearrangements in a multifocal and multifaceted manner. Our results open a new area of clinical genetics and human genetic research.