Over 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.

DD diagnostics improvement.

Understanding the pathogenic significance of concomitant 3q13.31 and 22q13.32-q13.33 microdeletions.

Ring 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.

We 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.

Multiple 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.