Article Text
Abstract
Introduction Phelan-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.
Methods Following 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.
Results WGS 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.
Conclusions Although 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.
- polymicrogyria
- SHANK3
- NFAM1
- TCF20
- topologically associating domains
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Footnotes
Contributors NK, MD, LX, MR performed WGS analysis. EE performed TAD and WES analysis. FA interpreted Brain MRI analysis. CZ assessed EEG finding. CM and MGD conducted clinical neurological evaluations and managed the patient. SiB and RG performed segregation analysis of the SRPX2 variant and X-inactivation analysis. MCB interpreted cytogenetics, array-CGH and FISH investigations. SB provided technical assistance to cytogenetic analysis. MCB and OZ designed the study. MCB, OZ, NK and EE contributed significantly to this study, wrote the article and critically discussed the final editing of the manuscript.
Funding MCB was supported by grants of the Italian Ministry of Health (Ricerca Corrente 2017). OZ was supported by Telethon Italy Grant GGP13060.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The study has E. Medea Scientific Institute Research Ethics Committee approval (Prot. no. 007/15-CE).
Provenance and peer review Not commissioned; externally peer reviewed.