BackgroundRing chromosome instability may influence a patient’s phenotype and challenge its interpretation.ResultsHere, we report a 4-year-old girl with a compound phenotype. Cytogenetic analysis revealed her karyotype to be 46,XX,r(22). aCGH identified a 180 kb 22q13.32 duplication, a de novo 2.024 Mb subtelomeric 22q13.32-q13.33 deletion, which is associated with Phelan-McDermid syndrome, and a maternal single gene 382-kb TUSC7 deletion of uncertain clinical significance located in the region of the 3q13.31 deletion syndrome. All chromosomal aberrations were confirmed by real-time PCR in lymphocytes and detected in skin fibroblasts. The deletions were also found in the buccal epithelium. According to FISH analysis, 8% and 24% of the patient’s lymphocytes and skin fibroblasts, respectively, had monosomy 22.ConclusionsWe believe that a combination of 22q13.32-q13.33 deletion and monosomy 22 in a portion of cells can better define the clinical phenotype of the patient. Importantly, the in vivo presence of monosomic cells indicates ring chromosome instability, which may favor karyotype correction that is significant for the development of chromosomal therapy protocols.Electronic supplementary materialThe online version of this article (10.1186/s13039-018-0375-3) contains supplementary material, which is available to authorized users.

IntroductionOver 20% of patients with developmental delay (DD) has copy number variations (CNV) of unknown significance. Some CNV may be associated with disease in a patient and also present in their apparently healthy parents. According to the two-hit model another CNV may contribute to phenotypic variation of such genomic disorders.ObjectivesDD diagnostics improvement.AimsUnderstanding the pathogenic significance of concomitant 3q13.31 and 22q13.32-q13.33 microdeletions.MethodsRing chromosome 22 was first detected by conventional cytogenetics. Microdeletions at 3q13.31 and 22q13.32–q13.33 were revealed by agilent technologies 60 K microarray and confirmed by qPCR. Ring chromosome was confirmed by FISH.ResultsWe present a four-year-old girl with del22q13.32-q13.33 resulted in a ring chromosome 22 and a single TUSC7 gene microdeletion at 3q13.31. The del22q13.32-q13.33 originated de novo, whereas del3q13.31 was inherited from healthy mother. The 22q13.32-q13.33 locus is associated with Phelan-McDermid syndrome (PHMDS, OMIM 606232). The patient demonstrated features both typical for the syndrome (psychomotor and speech development delay, autistic signs, aggression, sleep alteration, seizures) and atypical – attention deficit-hyperactivity disorder (ADHD), ventriculomegaly, and reduced size of cerebella hemispheres (Dandy-Walker variant). ADHD and ventriculomegaly were previously described in patients with del3q13.31 (OMIM 615433) but Dandy-Walker variant was observed in our patient for the first time. Possibly, atypical for PHMDS features, may result from trans-epistasis of microdeletions.ConclusionsMultiple CNVs in one patient complicate genotype-phenotype correlations due to possible overlapping phenotypes and/or modifying effect of variants. This study was supported by Russian Science Foundation, grant no. 16-15-10231.