Molecular mechanisms for subtelomeric rearrangements associated with the 9q34.3 microdeletion syndrome

Abstract

We characterized at the molecular level the genomic rearrangements in 28 unrelated patients with 9q34.3 subtelomeric deletions. Four distinct categories were delineated: terminal deletions, interstitial deletions, derivative chromosomes and complex rearrangements; each results in haploinsufficiency of the EHMT1 gene and a characteristic phenotype. Interestingly, 25% of our patients had de novo interstitial deletions, 25% were found with derivative chromosomes and complex rearrangements and only 50% were bona fide terminal deletions. In contrast to genomic disorders that are often associated with recurrent rearrangements, breakpoints involving the 9q34.3 subtelomere region are highly variable. Molecular studies identified three regions of breakpoint grouping. Interspersed repetitive elements such as Alu, LINE, long-terminal repeats and simple tandem repeats are frequently observed at the breakpoints. Such repetitive elements may play an important role by providing substrates with a specific DNA secondary structure that stabilizes broken chromosomes or assist in either DNA double-strand break repair or repair of single double-strand DNA ends generated by collapsed forks. Sequence analyses of the breakpoint junctions suggest that subtelomeric deletions can be stabilized by both homologous and nonhomologous recombination mechanisms, through a telomere-capture event, by de novo telomere synthesis, or multistep breakage-fusion-bridge cycles.

Genomic segmental duplications on the basis of the t(9;22) rearrangement in chronic myeloid leukemia

“…Interspersed repetitive elements such as Alu and LINE are commonly present at or near genomic breakpoints. Such repetitive elements may have an important role by providing substrates with a specific DNA secondary structure that stabilizes broken chromosomes, increasing the probability of rearrangements (Yatsenko et al, 2009).…”

A mosaic maternal splice donor mutation in the EHMT1 gene leads to aberrant transcripts and to Kleefstra syndrome in the offspring

“…2 The genetic causes of Kleefstra syndrome are heterozygous microdeletions in 9q34.3 and EHMT1 (euchromatic histone-lysine N-methyltransferase 1) point mutations, both leading to loss of function of the affected EHMT1 allele. 1,3 Parent-to-child transmission of Kleefstra syndrome appears to be very rare and was described only for three cases with 9q34.3 deletion 4,5 and one case with a balanced translocation. 5 All EHMT1 point mutations described so far have appeared de novo in the patients.…”

“…1,3 Parent-to-child transmission of Kleefstra syndrome appears to be very rare and was described only for three cases with 9q34.3 deletion 4,5 and one case with a balanced translocation. 5 All EHMT1 point mutations described so far have appeared de novo in the patients. 6 Here, we report on a patient with characteristic features of Kleefstra syndrome carrying a novel splice-site mutation in EHMT1.…”

An Evolutionary Biology Approach to Understanding Neurological Disorders

“…For example, CpG context elevates the mutation rate by an order of magnitude (Schmidt et al, 2008), non-B DNA structures induced by palindromic AT-rich repeats facilitate recurrent translocations on chromosomes 11 and 22 at positions 11q23 and 22q11 (Kurahashi et al, 2006), while interspersed repetitive elements such as Alu, LINE, long-terminal repeats, and simple tandem repeats are frequently observed at breakpoints in the 9q34.3 subtelomere region (Yatsenko et al, 2009). However, at any given point, multiple mechanisms are acting, making prediction of mutational site and frequency difficult (Arnheim & Calabrese, 2009).…”

“…The active nature of many human retrotransposons is therefore linked to disease-causing somatic and germline mutations (Collier & Largaespada, 2007;Wallace et al, 1991;Oldridge et al, 1999;Claverie-Martin et al, 2003). Repeats may also contribute to DNA secondary structures that are more prone to breakage (Yatsenko et al, 2009). One novel aspect of our increased understanding of the role of repetitive DNA sequence in de novo mutations, and our ability to detect such sequences, is that this information can now be used to predict rearrangements that will contribute to genomic disorders (Carvalho et al, 2010;Ou et al, 2011;Sharp et al, 2006).…”