Looks Can Be Deceiving: Diagnostic Power of Exome Sequencing in Debunking 15q11.2 Copy Number Variations

Abstract

Background/Objectives: The pathogenetic role of 15q11.2 Copy Number Variations (CNVs) remains contentious in the scientific community, as microdeletions and microduplications in this region are linked to neurodevelopmental disorders with variable expressivity. This study aims to explore the diagnostic utility of Exome Sequencing (ES) in a cohort of pediatric patients with 15q11.2 CNVs. Methods: We enrolled 35 probands with 15q11.2 microdeletions or microduplications from two genetic centers between January 2021 and January 2023. Chromosomal Microarray Analysis (CMA) and ES were performed with written consent obtained from all parents. Pathogenic variants were classified according to ACMG guidelines. Results: CMA identified additional pathogenic CNVs in 3 of 35 children (9%). Subsequent ES revealed likely pathogenic or pathogenic variants in 11 of 32 children (34%). Notably, a higher percentage of isolated autism spectrum disorder (ASD) diagnoses was observed in patients without other CNVs or point mutations (p = 0.019). Conclusions: The ES analysis provided a diagnostic yield of 34% in this pediatric cohort with 15q11.2 CNVs. While the study does not dismiss the contribution of the CNV to the clinical phenotype, the findings suggest that ES may uncover the underlying causes of neurodevelopmental disorders. Continuous monitoring and further genetic testing are recommended for all 15q11.2 CNV carriers to optimize clinical management and familial counseling.

Keywords: 15q11.2 microdeletion; 15q11.2 microduplication; BP1-BP2 CNVs; alternative diagnosis; double diagnosis; exome sequencing; rare diseases.

Figure 2

Trio-ES detection rate in isolated Autism Spectrum Disorder. Among 15q11.2 CNV carriers affected by isolated ASDs, the results of ES are displayed on the x-axis, while the number of patients is shown on the y-axis. ES did not identify any Likely Pathogenic or Pathogenic variants in any subjects; a Variant of Uncertain Significance was reported in only one patient. Points in Blue indicate patients without a diagnosis of ASDs, while points in Green indicate patients with a diagnosis of ASDs (see legend for details).

Figure 3

Diagnostic yield of Array CGH and trio-ES in 15q11.2 CNV carriers. In three out of 35 (9%) children CMA detected additional pathogenic or likely pathogenic genomic arrangements (CNV LP/P). ES showed a very high detection rate (31%) of pathogenic or likely pathogenic variants (WES LP/P). In further 4 patients (11%), a variant of uncertain significance has been reported (WES VOUS). In 17 patients (49%), the ES analysis was negative (WES neg).

Figure 1

Face pictures of some 15q11.2 CNV carriers with dysmorphic features. Neither the subgroup of 15q11.2 microdeletions nor the microduplication presented with recurrent features. Top row from left to right: Patient 4, Patient 25, Patient 8, Patient 7; middle row from left to right: Patient 20, Patient 23, Patient 15, Patient 17; bottom row from left to right: Patient 9, Patient 6, Patient 5, Patient 13.