The Growing Complexity of the Monosomy 1p36 Syndrome

Even before the first draft of the human reference genome and the genome-wide screening methods based on this reference became available, several recognizable ‘deletion syndromes’ were known to the medical genetics community. For instance, a syndrome characterized by distinct dysmorphic features, such as large anterior fontanels, microcephaly, brachycephaly, deep-set eyes, flat nose and nasal bridge, and a pointed chin was found in ∼1 out of 5,000 live births [Shapira et al., 1997; Slavotinek et al., 1999; Gajecka et al., 2007]. By classical karyotyping and FISH, a deletion in the 1p36 region of one of the chromosomes of the patient was detected. Thus, ‘deletion 1p36’ or ‘monosomy 1p36’ became the most common terminal deletion syndrome in humans. Patients with monosomy 1p36 often show hypotonia, brachycamptodactyly, short feet, intellectual disability, and speech problems. Less frequently, congenital heart defects, vision problems, including visual inattention, seizures, sensorineural deafness, gastrointestinal anomalies, hypothyroidism, and anomalies of the kidneys and the external genitalia are also observed [Battaglia, 1993]. Genome-wide aneuploidy screening with BAC-, oligonucleotide and SNP arrays revealed a remarkable variability in size and position of the terminal and interstitial deletions in these patients. These findings have been used to map and identify candidate genes for some of the clinical features of monosomy 1p36 patients [Jordan et al., 2015]. More detailed molecular cytogenetic studies with higher resolution arrays revealed an unexpected complexity of 1p36 rearrangements and gave rise to speculations as to its putative mechanism(s) of origin [Ballif et al., 2003; Zanardo et al., 2014; Gamba et al., 2015].

Although the 1p36 region contains several blocks of segmental duplications, the deletions in patients with monosomy 1p36 vary widely in size and share no common breakpoints [Ballif et al., 2003]. This means that these deletions in 1p36 are not recurrent and not likely the result of nonallelic homologous recombination [Sharp et al., 2005]. Using arrays consisting of tiling BAC-clones and PCR, Ballif et al. [2003] mapped deletion breakpoints and subsequently analyzed the sequences of the breakpoint junctions. In 1 case, a pure terminal 1p36 deletion was stabilized by telomeric repeat sequences, while 2 other cases had terminal deletions associated with cryptic interrupted inverted duplications. These inverted duplication/deletion breakpoints prompted the authors to propose a model based on premeiotic breakage-fusion-bridge (BFB) cycles in the germline [Ballif et al., 2003]. This would then produce gametes with terminal deletions associated with proximal inverted duplications.

Recently, 2 cases with monosomy 1p36 have been described in which multiple deletions, interspersed with diploid segments and flanked by a proximal duplication, were characterized by FISH and array-CGH [Zanardo et al., 2014; Gamba et al., 2015]. Notwithstanding the remarkable similarity of these rearrangements, the authors suggested 2 distinct mechanisms of origin: chromoanagenesis and chromothripsis. Chromoanagenesis is a mechanism by which a cell responds to a collapsed DNA replication fork by generating a double-strand break followed by DNA synthesis, during which templates are switched repeatedly [Holland and Cleveland, 2012]. The latter is also known as fork stalling and template switching (FoSTes) and may string segments of a single or multiple chromosomes together such that complex patterns of duplications, triplications, deletions, and diploid segments result [Poot and Haaf, 2015]. At the joining points of these segments, small regions of microhomology are generated, which serve as a ‘molecular signature’ of FoSTes. Alternatively, chromoanagenesis may involve microhomology-mediated break-induced repair, which will also produce small regions of microhomology at the joining points, similar to those resulting from FoSTes. A special form of chromoanagenesis is chromoanasynthesis, which produces no deletions but only duplications [Plaisancié et al., 2014].

To explain 5 deletions interspersed with diploid segments and flanked by a proximal duplication, Gamba et al. [2015] proposed chromothripsis as a possible cause. This mechanism is based on shattering of one or several chromosomes in many segments, which are subsequently fused together by nonhomologous end joining [Korbel and Campbell, 2013]. During this process, a few chromosomal segments may be lost, so that the final product will contain deletions. This fusion process does not involve the use of a DNA template. Consequently, no regions of microhomology are found at the joining points, and the segments are fused in random order [Kloosterman et al., 2011, 2012; Korbel and Campbell, 2013].

Thus far, 2 mechanisms for chromothripsis have been described: isolation and under-replication of one or several chromosomes in a micronucleus or a telomere crisis followed by BFB cycles, rupture of the nuclear envelope and kataegis [Maciejowski et al., 2015; Zhang et al., 2015]. The micronucleus-based mechanism involves microhomology-mediated break-induced repair and produces deletions alternating with diploid segments [Zhang et al., 2015]. Chromothripsis after telomere crisis and BFB cycles affects at least 2 chromosomes and produces strings of deletions, duplications and diploid segments [Maciejowski et al., 2015]. Premeiotic BFB cycles were earlier proposed as a possible cause of monosomy 1p36 [Ballif et al., 2003]. To decide whether chromoanagenesis, chromothripsis or any other mechanism of chromosomal rearrangements may underlay monosomy 1p36, the relative orientation and the sequences of the joining points of all involved chromosome segments have to be determined using high-resolution methods such as paired-end or mate-pair sequencing [Kloosterman et al., 2011, 2012; Korbel and Campbell, 2013]. Given the relatively high prevalence of the recognizable monosomy 1p36 syndrome in the population, this endeavor may serve as a paradigm for such studies. Their outcome may also guide analyses of, for instance, the deletion/duplication 9p syndrome or other cases of deletions with associated duplications [Di Bartolo et al., 2012; Krgovic et al., 2014].

Martin Poot