A multi-omics approach to characterize a deep intronic ARID1A deletion in Coffin-Siris syndrome

Schuhmann S, Bosch E, Fink A, Schüssler S, Uebe S, Wiesener A, Ekici AB, Alders MM, Popp B, Kerkhof J, Brockmann E, Sadikovic B, Rompel O, Trollmann R, Reis A, Vasileiou G (2026)

Publication Type: Journal article

Publication year: 2026

Journal

European Journal of Medical Genetics Elsevier

Book Volume: 82

Article Number: 105084

DOI: 10.1016/j.ejmg.2026.105084

Abstract

Pathogenic variants in BAF complex genes are linked to neurodevelopmental disorders, termed BAFopathies. Coffin-Siris syndrome (CSS) is the most well-defined BAFopathy caused by variants in several BAF subunit genes. ARID1A variants are responsible for 6-8% of CSS cases. We report a female individual with clinical and phenotypic manifestations suggestive of CSS. Trio exome sequencing failed to identify a causative variant. Short-read genome sequencing revealed a de novo 24 kb intronic deletion in A RID1A . Methylation analysis showed a BAFopathy-like profile supporting pathogenicity. Transcriptome analysis and RT-PCR detected a rare aberrant splicing event in a subset of ARID1A transcripts: the activation of a pseudoexon, resulting in a premature termination codon as the underlying pathomechanism. This is the first non-coding pathogenic alteration reported in ARID1A and the second in a CSS gene. This case highlights how the combination of genomic, transcriptomic and epigenomic data is crucial to improve diagnostic accuracy in unsolved cases.

Authors with CRIS profile

Sarah Eller Institute of Human Genetics Elisabeth Bosch Professur für Humangenetik Andreas Fink Lehrstuhl für Humangenetik Stephanie Schüssler Department of Paediatrics and Adolescent Medicine Steffen Uebe Institute of Human Genetics Arif Bülent Ekici Lehrstuhl für Humangenetik Emily Brockmann Lehrstuhl für Humangenetik Oliver Rompel Medizinische Fakultät Regina Trollmann Professur für Kinder- u. Jugendmedizin Schwerpunkt Neuropädiatrie André Wiesmann da Silva Reis Lehrstuhl für Humangenetik Georgia Vasileiou Institute of Human Genetics

Involved external institutions

Amsterdam University Medical Centers (Amsterdam UMC) / Amsterdam Universitair Medische Centra NL Netherlands (NL) Berliner Institut für Gesundheitsforschung in der Charité / Berlin Institute of Health at Charité (BIH) DE Germany (DE) London Health Sciences Centre CA Canada (CA)

How to cite

APA:

Schuhmann, S., Bosch, E., Fink, A., Schüssler, S., Uebe, S., Wiesener, A.,... Vasileiou, G. (2026). A multi-omics approach to characterize a deep intronic ARID1A deletion in Coffin-Siris syndrome. European Journal of Medical Genetics, 82. https://doi.org/10.1016/j.ejmg.2026.105084

MLA:

Schuhmann, Sarah, et al. "A multi-omics approach to characterize a deep intronic ARID1A deletion in Coffin-Siris syndrome." European Journal of Medical Genetics 82 (2026).

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