Chromoanagenesis Event Underlies a de novo Pericentric and Multiple Paracentric Inversions in a Single Chromosome Causing Coffin–Siris Syndrome

Abstract

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.

Complex genomic rearrangements: an underestimated cause of rare diseases

“…The precise junction information is necessary to phase multiple breakpoints, to position the rearranged genomic segments, and to pinpoint the interrupted gene(s). All of which are crucial for clinical interpretation because the emergence of disease is location-dependent through various mechanisms such as increased or decreased gene copy number [39][40][41], gene disruptions [12], or perturbed gene regulation [1,42,43]. An average human genome is thought to contain 2.9 rare (<1%) coding SVs on average, and 2% of all people carry rare SVs >1 Mb in size encompassing both balanced and complex rearrangements [25].…”

“…Historically, CGR breakpoints were inferred using fluorescence in situ hybridization (FISH), multi-color banding, as well as karyotyping and chromosomal microarray (CMA) [6]. Because genome sequencing (GS) methodologies have increased our ability to detect and interpret complex genomic events, a growing number of reports of clinically relevant CGRs with an unexpected level of complexity have been published in the scientific literature [7][8][9][10][11][12]. Hence, CGRs, that were once presumed to be 'ultra-rare' occurrences may be more common than originally thought.…”

“…Such an approach has been successfully used in a cohort of patients with specific rare genetic diseases [16,17] and in studies of patients with rare diseases without a molecular diagnosis [18]. Furthermore, using such complementary methodology has revealed additional complexities in seemingly simple chromosome rearrangements [10][11][12]. In all, using standardized analysis approaches, CGRs are not only underdetected but are also insufficiently characterized, making clinical interpretation challenging.…”

Clan genomics: From OMIM phenotypic traits to genes and biology

“…Mendelian condition such as Cornelia de Lange Syndrome (CDLS1; MIM #122470) or Coffin-Siris Syndrome (CSS1; MIM #135900) and due to interruption of noncoding gene sequences, NIPL and ARID1B respectively, and thus NOT revealed by cES (Grochowski et al, 2021;Plesser Duvdevani et al, 2020). Also, From the mutational mechanism perspective it is quite intriguing to observe the types of complex genomic DNA rearrangements, including chromothripsis, that have been reported in association with CRISPR-Cas9 gene editing (Kosicki et al, 2018;Leibowitz et al, 2021;Simeonov et al, 2019).…”

“…The complexity of genomic changes observed in cancer and in constitutional genomes can be extensive as evidenced by the phenomenon, of chromothripsis and chromoanasynthesis (Liu et al, 2011; Maher & Wilson, 2012; Stephens et al, 2011) and what has been more recently defined as chromoanagenesis (Crasta et al, 2012). Intriguingly the organismal phenotype with such chromothripsis‐like changes might be only a Mendelian condition such as Cornelia de Lange Syndrome (CDLS1; MIM #122470) or Coffin‐Siris Syndrome (CSS1; MIM #135900) and due to interruption of noncoding gene sequences, NIPL and ARID1B respectively, and thus NOT revealed by cES (Grochowski et al, 2021; Plesser Duvdevani et al, 2020). Also, From the mutational mechanism perspective it is quite intriguing to observe the types of complex genomic DNA rearrangements, including chromothripsis, that have been reported in association with CRISPR‐Cas9 gene editing (Kosicki et al, 2018; Leibowitz et al, 2021; Simeonov et al, 2019).…”