22q11.2 recurrent copy number variation-related syndrome: a retrospective analysis of our own microarray cohort and a systematic clinical overview of ClinGen curation.

backgroundChromosomal 22q11.2 dosage changes in the recurrent region can lead to a series of clinically variable pediatric syndromes. This study conducted a retrospective analysis of microarray tested cases with 22q11.2 recurrent copy number variations (CNVs) at our laboratory from September 2018 to August 2021, and provides a systematical clinical overview of ClinGen curation.

methodsThe data of 34 microarray tested cases with 22q11.2 recurrent CNVs at our laboratory from September 2018 to August 2021 were retrospectively analyzed, and the variant types, abnormal chromosome regions, clinical phenotypes, and follow-up information were evaluated and summarized. A ClinGen Dosage Sensitivity Map was retrieved for "22q11.2". The information of each 22q11.2 recurrent region was collected and systematically classified.

resultsWe reported 34 cases (including 18 22q11.2 microdeletion cases and 16 microduplication cases) from 8,465 microarrays. Of the 22q11.2 recurrent CNV-carried samples, 74% (25/34) comprised prenatal amniotic fluid or villus, and up to 50% (17/34) of the cases contained the proximal A-D interval. Across these 22q11.2 microdeletion samples, the congenital cardiovascular defect, which mainly included the tetralogy of fallot, ventricular septal defect, and patent foramen ovale, was identified as the most common feature (13/18, 72%). However, 22q11.2 microduplication cases exhibited a broad range of highly variable phenotypes, spanning from severe abnormality to mild characteristics and even the completely normal phenotype. This study also systematically reviewed the ClinGen dosage sensitivity curation on 22q11.2 recurrent regions, and found that A-D/A-B haploinsufficiency score reached "3", responsible for DiGeorge syndrome (DGS)/velocardiofacial syndrome (VCFS). Also, A-D/A-B triplosensitivity score "3" could further account for multiple variable phenotypes.

conclusionsTaken together, this study provides clinical overview of the ClinGen curation and data support for the American College of Medical Genetics and Genomics (ACMG) evaluation in the pathogenicity of each interval involved in 22q11.2 recurrent deletion and duplication. Certainly, more evidences on the genotype-phenotype contributions of different 22q11.2 recurrent CNVs need to be gathered.