Chromothripsis and ring chromosome 22: a paradigm of genomic complexity in the Phelan-McDermid syndrome (22q13 deletion syndrome)

Abstract

IntroductionPhelan-McDermid syndrome (PMS) is caused by SHANK3 haploinsufficiency. Its wide phenotypic variation is attributed partly to the type and size of 22q13 genomic lesion (deletion, unbalanced translocation, ring chromosome), partly to additional undefined factors. We investigated a child with severe global neurodevelopmental delay (NDD) compatible with her distal 22q13 deletion, complicated by bilateral perisylvian polymicrogyria (BPP) and urticarial rashes, unreported in PMS.MethodsFollowing the cytogenetic and array-comparative genomic hybridization (CGH) detection of a r(22) with SHANK3 deletion and two upstream duplications, whole-genome sequencing (WGS) in blood and whole-exome sequencing (WES) in blood and saliva were performed to highlight potential chromothripsis/chromoanagenesis events and any possible BPP-associated variants, even in low-level mosaicism.ResultsWGS confirmed the deletion and highlighted inversion and displaced order of eight fragments, three of them duplicated. The microhomology-mediated insertion of partial Alu-elements at one breakpoint junction disrupted the topological associating domain joining NFAM1 to the transcriptional coregulator TCF20. WES failed to detect BPP-associated variants.ConclusionsAlthough we were unable to highlight the molecular basis of BPP, our data suggest that SHANK3 haploinsufficiency and TCF20 misregulation, both associated with intellectual disability, contributed to the patient’s NDD, while NFAM1 interruption likely caused her skin rashes, as previously reported. We provide the first example of chromoanasynthesis in a constitutional ring chromosome and reinforce the growing evidence that chromosomal rearrangements may be more complex than estimated by conventional diagnostic approaches and affect the phenotype by global alteration of the topological chromatin organisation rather than simply by deletion or duplication of dosage-sensitive genes.

Insertional translocation involving an additional nonchromothriptic chromosome in constitutional chromothripsis: Rule or exception?

“…It is worthwhile to note that in all three cases, the chromothriptic event was associated with an insertional translocation involving an additional chromosome. Several examples of chromothriptic‐like events associated with insertional translocation have been recently reported in cases with multiple CNVs (Gu et al, ; Kato et al, ; Kurtas et al, ). Taking into consideration that depending on the sequencing resolution some insertional translocations may escape detection, these events are probably the rule rather than the exception (Slamova et al, ).…”

On the Complexity of Mechanisms and Consequences of Chromothripsis: An Update

“…In the virtually complete absence of any genetic imbalance, CC may co-occur with breakage of multiple genes or changes in their expression (Table 2; van Heesch et al, 2014; de Pagter et al, 2015; Bertelsen et al, 2016; Middelkamp et al, 2017). CC may include structural chromosomal abnormalities associated with genetic disorders (Table 2; Fontana et al, 2014; Genesio et al, 2015; Kurtas et al, 2018). In this case, the patient displays symptoms of an inherited disease.…”

“…Constitutional chromothripsis is generally characterised by fewer chromosome breaks and almost complete absence of deletions in comparison with malignant tumours (Figure 1; Kloosterman and Cuppen, 2013). A number of studies treat CCR cases with duplications of chromosome regions as chromothripsis (Table 2; Gamba et al, 2015; Wang et al, 2015; Del Rey et al, 2016; Kurtas et al, 2018). It is yet to be established, however, whether such genetic abnormalities in patients are cases of true chromothripsis or variations of other CCRs.…”

TCF 20 dysfunction leads to cortical neurogenesis defects and autistic‐like behaviors in mice

“…TCF20 is located in the chromosome 22q13.2 region, which is close to the Phelan-McDermid syndrome (PMS) candidate gene shank3 [21]. PMS, known as 22q13.3 deletion syndrome, involves a range of phenotypes, including global developmental delay, intellectual disability, neonatal hypotonia, autism, and autistic-like behaviors, which has caused PMS to be considered a syndromic form of ASD [22][23][24]. TCF20 mutations or microdeletions were also found in PMS patients [21,23,25].…”