Phenocopies of 22q11.2DS: revealing genetic diversity in clinically suspected 22q11.2 deletion syndrome

Abstract Background Although 22q11.2 deletion syndrome (22q11.2DS) is one of the most common microdeletion syndromes, a substantial proportion of patients with clinically suspected 22q11.2DS (clin22q11.2) remain without a definitive diagnosis. While CNVs other than the typical 22q11.2 deletion have been identified in patients with clin22q11.2 (defined here as phenocopies of 22q11.2DS, or phen22q11.2), SNVs associated with phen22q11.2 are less well defined. Results We aimed to investigate genetic variants associated with phen22q11.2 to achieve definitive diagnoses and improve clinical management in the clin22q11.2 cohort, while also comparing the phenotypic features of 22q11.2DS and phen22q11.2 to guide optimal diagnostic approaches. We assessed 336 consecutive pediatric patients from three centers presenting with clin22q11.2 according to Tobias criteria. Diagnostic testing included fluorescence in situ hybridization or multiplex ligation-dependent probe amplification in all patients. In subsets of patients, additional investigations were performed as clinically indicated, including but not limited to karyotyping, chromosomal microarray analysis, and/or exome sequencing (ES) with CNV detection. To identify phenotypic differences, Fisher’s exact test and Chi-squared test were performed. Genetic abnormalities were identified in 127 patients, including 88 patients diagnosed with 22q11.2DS. Phen22q11.2 was identified in 39 patients, including de novo variants in 12 patients. Several SNVs were detected, including variants in recurrently affected genes, such as CHD7 (n = 4), TBX1 (n = 2), JAG1 (n = 2), as well as variants in genes implicated in rare and ultra-rare diseases. We also described several rare and previously unreported clinical features associated with variants linked to phen22q11.2. No statistically significant phenotypic differences were observed between patients with phen22q11.2 and those with 22q11.2DS. Conclusions Phen22q11.2 is genetically and phenotypically heterogeneous. The results support the use of ES with CNV analysis as a first-tier, high-throughput diagnostic approach in clin22q11.2, as comprehensive genomic testing is essential for improving diagnostic accuracy and optimizing both genetic counseling and clinical management in this population.