Clinical phenotype, immunological abnormalities and genomic findings in patients with DiGeorge spectrum phenotype without 22q11.2 deletion

Abstract Background The phenotype of early embryonic fourth branchial arch defects encompasses a wide spectrum of clinical conditions including DiGeorge syndrome (DGS), velocardiofacial syndrome (VCFS), cono-truncal anomaly face syndrome (CFTAS). The majority of the patients have a 22q11.2 deletion. However, in 6-17% of patients the identification of a genetic cause remains unknown through FISH. In these patients, the clinical features and the immunological abnormalities are not well defined. Objective To describe the main genomic abnormalities, clinical features and immunological abnormalities of a cohort of patients resembling the 22q11.2 deletion phenotype in the absence of 22q11.2 locus alterations. Methods Eleven patients from unrelated non-consanguineous families with suspected 22q11.2 deletion syndrome according to Tobias criteria were enrolled. Array-Comparative Genomic Hybridization (Array-CGH) was performed in 10 patients. A phenotypic and immunological assessment was performed in all patients. Results The majority of patients had a phenotype overlapping with 22q11.2DS and immunological abnormalities suggestive of abnormalities in T-cell development, being severe in 2 of them. Most subjects suffered from recurrent infections. Clinically overt autoimmune manifestations were identified in 2 (18%) subjects. New pathogenic or likely pathogenic genomic regions associated to 22q11.2DS features were identified. Conclusion Patients with DGS-like phenotype share the same features of the classical 22q11.2 deletion syndrome associated with other rare genomic alterations. Severe forms of immunodeficiency may also be observed in this group.