Discovery of a Novel Likely Pathogenic Splice Site Variant of PACS1 in a Patient with Craniofacial Deformity, Developmental Delay, and Drug-Resistant Epilepsy
Background:
Treating epilepsy associated with genetic variants, particularly those co-occurring with developmental delay and congenital brain malformations, requires the efficient identification of pathogenic variants in individual patients. However, interpreting the vast amount of data generated by next-generation sequencing poses significant challenges. PACS1 syndrome, a rare genetic disorder characterized by developmental delay, intellectual disability, distinct craniofacial features, and seizures, serves as a valuable model for studying rare disease genetics. The mutation spectrum in PACS1 and its clinical implications continue to expand. Using artificial intelligence (AI)-assisted deep learning tools, we identified a novel splice site variant in PACS1 in a patient presenting with characteristic craniofacial deformity, developmental delay, and drug-resistant epilepsy (DRE).
Design/Methods:
Whole-exome sequencing was conducted on a 28-year-old male patient with a history of craniofacial deformity, developmental delay, and DRE. It revealed a splicing site variant in PACS1 (NM_018026.4(PACS1) c.1199+5G>A), and its functional impact was predicted using SpliceAI and MaxEntScan.
Results:
Both SpliceAI and MaxEntScan predicted the variant to have a high likelihood of causing aberrant splicing. SpliceAI generated a delta score of 0.64 for donor loss and 0.21 for acceptor loss, while Pangolin produced a delta score of 0.82 for splice loss. MaxEntScan also yielded scores 0.89 for donor loss. These strong predictive scores indicate a significant disruption of normal splicing, suggesting the variant’s pathogenicity and its likely contribution to the patient’s phenotype. Additionally, we analyzed other variants reported in close vicinity to this splicing site. None of these variants exhibited similarly high predictive scores, further supporting the likelihood that the novel splicing site variant (c.1199+5G>A) is potentially pathogenic.
Conclusions:
The identification of the novel PACS1 splicing site mutation (c.1199+5G>A) broadens our understanding of the genotype-phenotype associations in PACS1-related disorders. This discovery underscores the critical role of splicing site mutations in rare genetic syndromes and their contribution to complex neurodevelopmental disorders.
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