Abstract
A growing number of genetic neurodevelopmental disorders are known to be associated with unique genomic DNA methylation patterns, called episignatures, which are detectable in peripheral blood. The intellectual developmental disorder, X-linked, syndromic, Armfield type (MRXSA) is caused by missense variants in FAM50A. Functional studies revealed the pathogenesis to be a spliceosomopathy that is characterized by atypical mRNA processing during development. In this study, we assessed the peripheral blood specimens in a cohort of individuals with MRXSA and detected a unique and highly specific DNA methylation episignature associated with this disorder. We used this episignature to construct a support vector machine model capable of sensitive and specific identification of individuals with pathogenic variants in FAM50A. This study contributes to the expanding number of genetic neurodevelopmental disorders with defined DNA methylation episignatures, provides an additional understanding of the associated molecular mechanisms, and further enhances our ability to diagnose patients with rare disorders.
Highlights
Mendelian neurodevelopmental disorders usually present with developmental delay (DD), intellectual disability (ID), and/or congenital anomalies (CA)
Over 50 genes and more than 42 neurodevelopmental conditions are currently described with associated DNA methylation signatures, referred to as episignatures or EpiSigns
Many of the related genes have a regulatory role in the epigenetic machinery; such as histone modification, DNA methylation, or chromatin remodeling
Summary
Mendelian neurodevelopmental disorders usually present with developmental delay (DD), intellectual disability (ID), and/or congenital anomalies (CA). These syndromes are often associated with complex and overlapping symptoms including overgrowth, aberrant craniofacial features, seizure, and neurological abnormalities, which may complicate clinical diagnosis [1]. Considering all congenital anomalies, 8% of individuals are estimated to have a genetic disorder before adulthood [3]. Conventional genetic testing, including the analysis of sequence and copy number variants (CNVs) and comprehensive genome-wide methods such as whole exome sequencing (WES), leaves a substantial proportion of subjects unresolved [4]. Genetic analysis in patients with a confirmed clinical diagnosis often yields no significant genetic findings or results in genetic variants of unknown clinical significance (VUS)
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