Journal
FRONTIERS IN GENETICS
Volume 12, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fgene.2021.708348
Keywords
genomic inversions; structural variation; complex genomic rearrangement (CGR); chromothripsis; chromoplexy; microhomology-mediated break-induced replication (MMBIR)
Categories
Funding
- United States National Institute of General Medical Sciences [NIGMS R01 GM132589]
- Swedish Brain Foundation [FO2020-0351]
- National Institute for Neurological Disorders and Stroke [NINDS R35 NS105078]
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Chromoanagenesis refers to catastrophic mutagenic processes creating complex chromosome rearrangements, with a case study of a 5-year-old female with Coffin-Siris syndrome 1 revealing multiple inversions on chromosome 6, disrupting the ARID1B gene responsible for the disease trait. The study highlights the importance of using multiple technologies to understand complex structural variants and their impact on genetic diseases.
Chromoanagenesis is a descriptive term that encompasses classes of catastrophic mutagenic processes that generate localized and complex chromosome rearrangements in both somatic and germline genomes. Herein, we describe a 5-year-old female presenting with a constellation of clinical features consistent with a clinical diagnosis of Coffin-Siris syndrome 1 (CSS1). Initial G-banded karyotyping detected a 90-Mb pericentric and a 47-Mb paracentric inversion on a single chromosome. Subsequent analysis of short-read whole-genome sequencing data and genomic optical mapping revealed additional inversions, all clustered on chromosome 6, one of them disrupting ARID1B for which haploinsufficiency leads to the CSS1 disease trait (MIM:135900). The aggregate structural variant data show that the resolved, the resolved derivative chromosome architecture presents four de novo inversions, one pericentric and three paracentric, involving six breakpoint junctions in what appears to be a shuffling of genomic material on this chromosome. Each junction was resolved to nucleotide-level resolution with mutational signatures suggestive of non-homologous end joining. The disruption of the gene ARID1B is shown to occur between the fourth and fifth exon of the canonical transcript with subsequent qPCR studies confirming a decrease in ARID1B expression in the patient versus healthy controls. Deciphering the underlying genomic architecture of chromosomal rearrangements and complex structural variants may require multiple technologies and can be critical to elucidating the molecular etiology of a patient's clinical phenotype or resolving unsolved Mendelian disease cases.
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