Somatic Loss of BCLAF-1 in an Encephalocele Secondary to Idiopathic Intracranial Hypertension

Introduction: Idiopathic intracranial hypertension (IIH), characterized by increased intracranial pressure, leads to headaches, tinnitus, and vision loss. Severe complications like cerebrospinal fluid (CSF) leaks, encephaloceles and meningitis have also been documented. Despite extensive research, the pathophysiology and genetic causes of IIH remain largely unknown. Although IIH is primarily sporadic, familial cases have been reported, but no specific genomic drivers have been identified. Given the predominantly sporadic and late-onset nature of IIH, our study aims to investigate the involvement of somatic mechanisms that might contribute to its development. Here we report the clinical features and somatic genomic profile of a 70-year-old female who was found to have a right-sided nasoethmoidal encephalocele after she was investigated for new seizures. Magnetic resonance imaging revealed empty sella with a likely diagnosis of IIH. She did not have a history of trauma and described long standing rhinorrhoea which had recently stopped. Her significant past medical history included history of morbid obesity. There was no known familial history of IIH. Patient underwent Endoscopic Endonasal Approach (EEA) for resection of the encephalocele, which was confirmed by pathology. The lesion and blood samples were also sent for Whole Exome Sequencing (WES).

Methods: WES was conducted on both the lesion and matched blood samples using the IDT xGen Exome Research Panel Version 1 with additional spike-ins, and sequencing was performed at the Yale Center for Genome Analysis (YCGA) on Illumina NovaSeq 600 WES systems, producing 2 × 101-bp reads and yielding high mean coverage of 266.6x for the tumor and 116.9x for the blood samples. The downstream analysis to identify somatic single nucleotide variations (SNV), short insertion-deletions (INDEL) and copy number variations (CNV) was performed as previously reported.

Results: Somatic analysis of WES data revealed 5 SNV/INDELs, including a stop-gain mutation in the BCLAF1 gene (NM_001077440, p.R748X). Somatic CNV analysis didn’t reveal any events.

Discussion: There is limited characterization of IIH and acquired encephalocele’s genetic landscapes. To our knowledge, this is the first study investigating the somatic genomic profile of IIH and identifying a somatic loss-of-function mutation on BCLAF1 gene in the sampled brain tissue. BCLAF1, located on 6q23.3, regulates intrinsic apoptosis pathway, upregulates TP53, Bax, caspase-3, and HIF-1a transcription. BCLAF1 is also linked to DNA-damage response (DDR), positive transcription regulation, and negative regulation of DNA-templated transcription. A stop-gain BCLAF1 mutation hinders cell apoptosis, promoting proliferation and growth. Further large-scale studies investigating the involvement of somatic genomic alterations in the pathophysiology of IIH are warranted to further investigate the interaction of HIF, BCL2, and BCLAF1 in IIH. These results suggest a phenotype characterized by cell proliferation, DDR and apoptosis evasion with decreased angiogenesis, thereby proposing a link between abnormal cell proliferation and IIH.

Publication History

Article published online:
07 February 2025