Human subtelomeric copy number gains suggest a DNA replication mechanism for formation: beyond breakage–fusion–bridge for telomere stabilization

Abstract

Constitutional deletions of distal 9q34 encompassing the EHMT1 (euchromatic histone methyltransferase 1) gene, or loss-of-function point mutations in EHMT1, are associated with the 9q34.3 microdeletion, also known as Kleefstra syndrome [MIM#610253]. We now report further evidence for genomic instability of the subtelomeric 9q34.3 region as evidenced by copy number gains of this genomic interval that include duplications, triplications, derivative chromosomes and complex rearrangements. Comparisons between the observed shared clinical features and molecular analyses in 20 subjects suggest that increased dosage of EHMT1 may be responsible for the neurodevelopmental impairment, speech delay, and autism spectrum disorders revealing the dosage sensitivity of yet another chromatin remodeling protein in human disease. Five patients had 9q34 genomic abnormalities resulting in complex deletion-duplication or duplication-triplication rearrangements; such complex triplications were also observed in six other subtelomeric intervals. Based on the specific structure of these complex genomic rearrangements (CGR) a DNA replication mechanism is proposed confirming recent findings in C elegans telomere healing. The end-replication challenges of subtelomeric genomic intervals may make them particularly prone to rearrangements generated by errors in DNA replication.

Mutation Spectra of Histone Methyltransferases With Canonical SET Domains and EZH2-Targeted Therapy

“…Germline deletion of the EHMT1 gene at human chromosome 9q34.3 has been detected in Kleefstra syndrome, whereas germline duplication and multiple rearrangements of the same region occur in 9q34.3 duplication syndrome, which presents as autism and speech delay, among others [29].…”

Autism throughout genetics: Perusal of the implication of ion channels

“…This region contains the CACNA1B gene, and the 3′ region of EHMT1 gene implicated in Kleefstra syndrome, which is a genetic disorder characterized by intellectual disabilities, infantile hypotonia, severe delay in expressive language, and facial dysmorphism associated with other clinical signs. However, this duplication was described by the author as “benign” because it was also found in the control individual (Yatsenko et al., 2012; Table 3). …”

Translesion Polymerases Drive Microhomology-Mediated Break-Induced Replication Leading to Complex Chromosomal Rearrangements

“…According to current models (Hastings et al, 2009a; Hastings et al, 2009b), MMBIR is initiated by DNA breakage generating a single DNA end, and proceeds with multiple template switches at positions of microhomologies that could be as short as 1-3bp, leading to varying levels of amplification and rearrangements (Lee et al, 2007; Liu et al, 2011a; Carvalho et al, 2013; Carvalho et al, 2011; Beck et al, 2015). The MMBIR model has since been used to explain telomere healing (Lowden, et al, 2011; Yatsenko, et al, 2012) and CGRs in a number of diseases including cancer (Lawson et al, 2011; Vissers et al, 2009; Wang et al, 2015). In addition, MMBIR-like events have been described in various model systems including bacteria (Slack et al, 2006; Lin et al, 2011), yeast (Payen et al, 2008), Arabidopsis (Kwon et al, 2010; Marechal et al, 2009), Caenorhabditis elegans (Meier et al, 2014), and mouse embryonic stem cells (Arlt et al, 2012).…”