Episignature leads to diagnosis and reclassification of DYRK1A variant in a child with syndromic neurodevelopmental disorder: a case report.

BACKGROUND

Neurodevelopmental disorders (NDDs) are genetically heterogeneous, and standard genomic testing frequently yields variants of uncertain significance (VUS) or misses cryptic structural variants. Episignature analysis, which detects disorder specific genome-wide DNA methylation patterns, has emerged as a functional tool to resolve diagnostic uncertainty.

CASE PRESENTATION: We report a 7-year-old female with global developmental delay, autism spectrum disorder, epilepsy, microcephaly, and a distinctive facial gestalt. Initial trio whole-exome sequencing identified inconclusive VUSs in CAD and POLR1A. A therapeutic trial of uridine for the CAD-related variants provided only transient benefit. Genome-wide DNA methylation analysis via EpiSign revealed a positive result for the episignature for Intellectual Developmental Disorder, Autosomal Dominant 7 (MRD7), associated with DYRK1A haploinsufficiency. Guided by this result, trio whole-genome sequencing identified a de novo heterozygous deletion involving exon 5 of DYRK1A. The exact breakpoints were chr21:38,852,074-38,856,009 (GRCh37/hg19) and chr21:39,044,532-39,048,467 (GRCh38/hg38). This variant was reclassified from VUS to likely pathogenic based on concordant episignatures findings, clinical phenotype, and de novo occurrence.

CONCLUSION

This case highlights the utility of episignature analysis to help diagnose NDD patients, guide further molecular diagnostic testing, and as a functional assay to aid variant reclassification. Integration of epigenomic profiling with standard of care testing can shorten the diagnostic odyssey, prevent unnecessary interventions, and directly inform clinical management in patients with unresolved NDDs.