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Diagnostic utility of DNA methylation analysis in genetically unsolved pediatric epilepsies and CHD2 episignature refinement.

Christy W LaFlammeCassandra RastinSoham SenguptaHelen E PenningtonSophie J Russ-HallAmy L SchneiderEmily S BonkowskiEdith P Almanza FuerteTalia J AllanMiranda Perez-Galey ZaluskyJoy GoffenaSophia B GibsonDenis M NyagaNico LiefferingMalavika HebbarEmily V WalkerDaniel DarnellScott R OlsenPandurang KolekarMohamed Nadhir DjekidelWojciech RosikiewiczHaley McConkeyJennifer KerkhofMichael A LevyRaissa RelatorDorit LevTally Lerman-SagieKristen L ParkMariëlle AldersGerarda CappuccioNicolas ChatronLeigh DemainDavid GenevieveGaëtan LescaTony RoscioliDamien SanlavilleMatthew L TedderSachin GuptaElizabeth A JonesMonika Weisz-HubshmanShamika KetkarHongzheng DaiKim Carlyle WorleyJill Anne RosenfeldHsiao-Tuan Chaonull nullGeoffrey A NealeGemma Louise Carvillnull nullZhaoming WangSamuel Frank BerkovicLynette G SadleirDanny E MillerIngrid E SchefferBekim SadikovicHeather C Mefford
Published in: Nature communications (2024)
Sequence-based genetic testing identifies causative variants in ~ 50% of individuals with developmental and epileptic encephalopathies (DEEs). Aberrant changes in DNA methylation are implicated in various neurodevelopmental disorders but remain unstudied in DEEs. We interrogate the diagnostic utility of genome-wide DNA methylation array analysis on peripheral blood samples from 582 individuals with genetically unsolved DEEs. We identify rare differentially methylated regions (DMRs) and explanatory episignatures to uncover causative and candidate genetic etiologies in 12 individuals. Using long-read sequencing, we identify DNA variants underlying rare DMRs, including one balanced translocation, three CG-rich repeat expansions, and four copy number variants. We also identify pathogenic variants associated with episignatures. Finally, we refine the CHD2 episignature using an 850 K methylation array and bisulfite sequencing to investigate potential insights into CHD2 pathophysiology. Our study demonstrates the diagnostic yield of genome-wide DNA methylation analysis to identify causal and candidate variants as 2% (12/582) for unsolved DEE cases.
Keyphrases
  • copy number
  • genome wide
  • dna methylation
  • mitochondrial dna
  • gene expression
  • peripheral blood
  • healthcare
  • high resolution
  • single molecule
  • mass spectrometry
  • risk assessment
  • circulating tumor
  • young adults