Discovery of a DNA methylation profile in individuals with Sifrim-Hitz-Weiss syndrome

• DOI: 10.1016/j.ajhg.2024.12.020
• Publication Date: 2025-01-16T15:48:32Z
• Authors: Karim Karimi; Yael Lichtenstein; Jack Reilly; Haley McConkey; Raissa Relator; Michael A. Levy; Jennifer Kerkhof; Arjan Bouman; Joseph D. Symonds; Jamal Ghoumid; Thomas Smol; Katie Clarkson; Katy Drazba; Raymond J. Louie; Valancy Miranda; Cathleen McCann; Jamie Motta; Emily Lancaster; Suzanne Sallevelt; Richard Sidlow; Jennifer Morrison; Mark Hannibal; Jessica O'Shea; Victor Marin; Chitra Prasad; Chirag Patel; Salmo Raskin; Seco Moro Maria-N...; Aranzazú Diaz de ...; Daphna Marom; Tali Barkan; Boris Keren; Celine Poirsier; Lior Cohen; Estelle Colin; Kathleen Gorman; Emily Gallant; Leonie A. Menke; Irene Valenzuela ...; Natalie Hauser; Ingrid M. Wentzensen; Julia Rankin; Peter D. Turnpenny; Philippe M. Campeau; Tugce B. Balci; Matthew L. Tedder; Bekim Sadikovic; Karin Weiss
• Keywords: Neurology; variable expressivity; autism; 610; Genetics and Genomics; methylation; neurodevelopmental; chromatin remodeler; truncating; ADNP; CHD4; compound heterozygous

Pathogenic heterozygous variants in CHD4 cause Sifrim-Hitz-Weiss syndrome, a neurodevelopmental disorder associated with brain anomalies, heart defects, macrocephaly, hypogonadism, and additional features with variable expressivity. Most individuals have non-recurrent missense variants, complicating variant interpretation. A few were reported with truncating variants, and their role in disease is unclear. DNA methylation episignatures have emerged as highly accurate diagnostic biomarkers in a growing number of rare diseases. We aimed to study evidence for the existence of a CHD4-related DNA methylation episignature. We collected blood DNA samples and/or clinical information from 39 individuals with CHD4 variants, including missense and truncating variants. Genomic DNA methylation analysis was performed on 28 samples. We identified a sensitive and specific DNA methylation episignature in samples with pathogenic missense variants within the ATPase/helicase domain. The same episignature was observed in a family with variable expressivity, a de novo variant near the PHD domain, variants of uncertain significance within the ATPase/helicase domain, and a sample with compound heterozygous variants. DNA methylation data revealed higher percentages of shared probes with BAFopathies, CHD8, and the terminal ADNP variants encoding a protein known to form the ChAHP complex with CHD4. Truncating variants, as well as a sample with a recurrent pathogenic missense variant, exhibited DNA methylation profiles distinct from the ATPase/helicase domain episignature. These DNA methylation differences, together with the distinct clinical features observed in those individuals, provide preliminary evidence for clinical and molecular sub-types in the CHD4-related disorder.