ARID1A gene variants and fetal hydrocephalus: First evidence of mRNA decay escape

Germline variants in ARID1A have been associated with the so-called BAFopathies, including Coffin-Siris syndrome, which is characterized by hypertrichosis, short fifth finger, thin upper lip, and thick lower lip, is associated with a unique episignature. Hydrocephalus has not been considered part of BAFopathy until recently, when ARID1A variants were implicated in prenatal-onset hydrocephalus. It remains unknown whether ARID1A-associated hydrocephalus is linked to a specific class of variants and whether it exhibits an episignature comparable to that of BAFopathies. We conducted genomic and epigenomic analyses on a fetus diagnosed with severe hydrocephalus on prenatal ultrasound at 19 weeks. After detailed genetic counseling, the pregnancy was terminated at 21 weeks. The delivered fetus exhibited short fifth fingers, thin upper lip, and thick lower lip. Postmortem exome sequencing using umbilical cord blood identified a de novo heterozygous frameshift variant in the last exon of ARID1A (NM_006015.6:c.5259_5262dupGTCT, p.(Ser1755Valfs∗2)). The frameshift variant in the last exon was expected to escape nonsense-mediated mRNA decay (NMD), and we did confirm this through RNA-seq. Concurrent episignature analysis by nanopore sequencing and a support vector machine-based classifier showed that the fetus maps to the BAFopathy group rather than a separate position on the UMAP. Genotype-phenotype correlation analysis of unpublished data from previous reports regarding hydrocephalus and potential NMD escape, with input from the original authors, indicated that the association remains ambiguous. Hence, ARID1A-associated hydrocephalus occurs within the broader clinical and epigenomic spectrum of BAFopathies, but a distinct genetic mechanism caused by NMD escape is unlikely to play a role.