Background: Parental imprinting plays a crucial role in epigenetic regulation and is increasingly recognized for its involvement in neurodevelopmental disorders. Although ATP8A2 is considered a non-imprinted gene; However, the marked phenotypic variability observed across related disorders suggests that additional regulatory layers may influence its expression. Methods: We investigated the imprinting-like status of ATP8A2 through functional analyses of a splicing variant (c.1580-3C>G) identified in a patient diagnosed with Cerebellar Ataxia, Mental Retardation, and Disequilibrium syndrome type 4 (CAMRQ4). Sanger sequencing was used to assess allelic expression and identify aberrant transcripts. Results: Our analyses revealed an allelic expression imbalance suggestive of parental imprinting of ATP8A2. Moreover, Sanger sequencing led to the identification of a novel ATP8A2–RAB3GAP2 chimeric transcript, pointing to a previously unreported transcriptional event, the functional relevance of which remains to be determined. Conclusions: These findings indicate that ATP8A2 may be subject to imprinting-like regulation and involved in atypical splicing events with unknown significance. This highlights the need for further investigation into the epigenetic and transcriptional complexity of ATP8A2-related neurodevelopmental disorders.

Accurate detection of BRCA1 and BRCA2 variants is essential for breast cancer diagnosis. However, the large size of these genes poses challenges for comprehensive analysis using short-read sequencing, which is generally limited to coding regions and may miss deep intronic and structural variants. This study evaluated the performance of Oxford Nanopore long-read sequencing (ONT-LRS) for comprehensive BRCA1 and BRCA2 analysis and compared its diagnostic yield with Ion Torrent sequencing. In this retrospective study, DNA samples from 27 individuals with breast cancer were initially analysed using Ion Torrent sequencing according to standard clinical workflows. Full BRCA1 and BRCA2 genes were subsequently amplified by long-range PCR and sequenced on R10.4.1 flow cells. Variants identified by ONT-LRS were compared with those detected by Ion Torrent. High concordance was observed between ONT-LRS and Ion Torrent for exonic single-nucleotide variants. Importantly, ONT-LRS identified additional variants not detected by Ion Torrent, including a deep intronic variant predicted to alter splicing and one structural variant. This study suggest that ONT-LRS extends the diagnostic capabilities of short-read sequencing by enabling accurate detection of BRCA1 and BRCA2 deep intronic and structural variants that may otherwise be overlooked, with potential implications for patient management and family counselling.