Abstract
The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans and is the result of a recurrent 1.5 to 2.5 Mb deletion, encompassing approximately 20–40 genes, respectively. The clinical presentation of the typical deletion includes: Velocardiofacial, Di George, Opitz G/BBB and Conotruncalanomaly face syndromes. Atypical deletions (proximal, distal or nested) are rare and characterized mainly by normal phenotype or mild intellectual disability and variable clinical features. The pathogenetic mechanisms underlying this disorder are not completely understood. Because the 22q11.2 region harbours genes coding for transcriptional factors and chromatin remodelers, in this study, we performed analysis of genome-wide DNA methylation of peripheral blood from 49 patients with 22q11.2DS using the Illumina Infinium Methylation EPIC bead chip arrays. This cohort comprises 43 typical, 2 proximal and 4 distal deletions. We demonstrated the evidence of a unique and highly specific episignature in all typical and proximal 22q11.2DS. The sensitivity and specificity of this signature was further confirmed by comparing it to over 1500 patients with other neurodevelopmental disorders with known episignatures. Mapping the 22q11.2DS DNA methylation episignature provides both novel insights into the molecular pathogenesis of this disorder and an effective tool in the molecular diagnosis of 22q11.2DS.
Highlights
The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans, with an incidence in about 1/4000 live births [1]
Our group and others have demonstrated that a growing number of Mendelian genetic disorders exhibit DNA methylation episignatures as highly sensitive and specific biomarkers in the peripheral blood of affected individuals [12,13,14,15,16,17,18,19,20,21]. These genome-wide DNA methylation profiles currently include over 40 rare disorders and represent effective biomarkers for the diagnosis of patients across a broadening range of neurodevelopmental genetic conditions, as well as a reflex functional assay for patients with ambiguous genetic findings or clinical phenotypes [22]
All samples were plotted using hierarchical clustering and multidimensional scaling to determine if cases used for training remained segregated with cases that were not, and to ensure that all cases remained separate from controls
Summary
The 22q11.2 deletion syndrome (22q11.2DS) is the most common genomic disorder in humans, with an incidence in about 1/4000 live births [1]. Our group and others have demonstrated that a growing number of Mendelian genetic disorders exhibit DNA methylation episignatures as highly sensitive and specific biomarkers in the peripheral blood of affected individuals [12,13,14,15,16,17,18,19,20,21] These genome-wide DNA methylation profiles currently include over 40 rare disorders and represent effective biomarkers for the diagnosis of patients across a broadening range of neurodevelopmental genetic conditions, as well as a reflex functional assay for patients with ambiguous genetic findings or clinical phenotypes [22]. Our secondary objective was to evaluate if methylation alteration may impact genes potentially relevant in the pathogenesis of the complex 22q11.2DS phenotype
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