Molecular and phenotypic characterization of ring chromosome 22 in two unrelated patients

We report on the cytogenetic and molecular characterization of a constitutional de novo ring chromosome 22 (r(22)) in 2 unrelated patients with emphasis on different hypotheses proposed to explain the phenotypic variability characterizing this genomic disorder. In both patients, molecular investigations using FISH and array-CGH techniques revealed a 22q terminal deletion involving the 22q13.33 critical region. The size of the deletion was estimated to at least 1.35 Mb in the first proband and to only 300 kb in the second. They both exhibited the major features of r(22) syndrome, but the first patient was more profoundly affected. He had a more severe phenotype, further complicated by behavioral anomalies, autistic-like features with abnormal EEG pattern and brain MRI profile. Haploinsufficiency of the SHANK3 gene, lying in the minimal critical region, is nowadays considered as responsible for most neurobehavioral anomalies. Nevertheless, phenotypic severity and occurrence of additional features in the first patient suggest a potential involvement of one or more specific gene(s) located proximally to SHANK3 (as PLXNB2, PANX2, ALG12 or MLC1), acting either independently of it or by regulating or promoting its expression and thus disrupting its function when deleted.