Evaluation of DNA Methylation Episignatures for Diagnosis and Phenotype Correlations in 42 Mendelian Neurodevelopmental Disorders

Abstract

Genetic syndromes frequently present with overlapping clinical features and inconclusive or ambiguous genetic findings which can confound accurate diagnosis and clinical management. An expanding number of genetic syndromes have been shown to have unique genomic DNA methylation patterns (called ''episignatures''). Peripheral blood episignatures can be used for diagnostic testing as well as for the interpretation of ambiguous genetic test results. We present here an approach to episignature mapping in 42 genetic syndromes, which has allowed the identification of 34 robust disease-specific episignatures. We examine emerging patterns of overlap, as well as similarities and hierarchical relationships across these episignatures, to highlight their key features as they are related to genetic heterogeneity, dosage effect, unaffected carrier status, and incomplete penetrance. We demonstrate the necessity of multiclass modeling for accurate genetic variant classification and show how disease classification using a single episignature at a time can sometimes lead to classification errors in closely related episignatures. We demonstrate the utility of this tool in resolving ambiguous clinical cases and identification of previously undiagnosed cases through mass screening of a large cohort of subjects with developmental delays and congenital anomalies. This study more than doubles the number of published syndromes with DNA methylation episignatures and, most significantly, opens new avenues for accurate diagnosis and clinical assessment in individuals affected by these disorders.

Episignatures stratifying ADNP syndrome show modest correlation with phenotype

“…Here we replicated and expanded earlier findings [15][16][17] of DNA methylation changes in ADNP syndrome. The mechanisms leading to these methylation changes are still unknown.…”

DNA methylation epi-signature is associated with two molecularly and phenotypically distinct clinical subtypes of Phelan-McDermid syndrome

“…However, the direct role of this methylation alteration on the pathophysiology of many of these diseases still needs further investigation. Our group has previously identified epi-signatures that can be used to specifically diagnose subjects with a variety of neurodevelopmental conditions, including syndromes that may clinically overlap with PHMDS [ 22 ]. The use of DNA methylation signatures can help solve many clinically ambiguous cases presenting with a neurodevelopmental phenotype.…”

“…Genomic DNA methylation profiles in peripheral blood, referred to as DNA methylation epi-signatures, have been associated with many human traits, including age, sex and disease status [ 18 – 21 ]. More recently, we and others have reported evidence of highly sensitive and specific peripheral blood epi-signatures associated with genetic mutations in a growing number of genes and genetic syndromes associated with developmental delay/intellectual disabilities and multiple congenital anomalies [ 22 – 25 ]. In addition, microarray-based genomic DNA methylation assessment has enabled simultaneous detection of imprinted disorders and Fragile X syndrome, which is often within the spectrum of differential diagnoses of these neurodevelopmental syndromes [ 26 , 27 ].…”

The emerging role of chromatin remodelers in neurodevelopmental disorders: a developmental perspective

“…When these epigenetic changes are maintained throughout development and across cell-types, these so called 'episignatures' can be used as biomarkers for the diagnosis of NDDs using easily accessible tissues such as peripheral blood [89][90][91][92]. Indeed, several very recent studies have already showed the potential for using disease-specific episignatures as diagnostic tool for NDDs, including patients with a known diagnosis as well as patients carrying variants of unknown significance [93][94][95].…”