Germline Whole-Gene Deletion of SDHA in a Carotid Body Paraganglioma Identified by Whole-Genome Sequencing and Confirmed by MLPA: A Case Report and Review of the Literature

Background : Carotid body paragangliomas are frequently associated with germline variants in succinate dehydrogenase ( SDH ) genes. Among these, SDHA variants are particularly challenging to diagnose due to low penetrance and the presence of highly homologous pseudogenes. Standard diagnostic workflows, including whole-exome sequencing and targeted panels, often fail to detect large structural variants, such as whole-gene deletions, leading to potential underdiagnosis. This case is the first to report a germline whole-gene deletion of SDHA identified via whole-genome sequencing (WGS), providing definitive physical evidence of the Knudson two-hit hypothesis through the somatic loss of the remaining allele in the tumor tissue. Case presentation : A 63-year-old female presented with a 2-cm, left carotid body tumor. There was no relevant family history. The tumor was successfully resected, and histopathology confirmed a paraganglioma. While immunohistochemistry showed a loss of both SDHA and SDHB expression, WGS of peripheral blood revealed what is, to our knowledge, the first reported germline whole-gene deletion of the SDHA gene (copy number ≈ 1.1) in the region chr5:210,651–314,171. Notably, this type of large structural variant is potentially elusive to standard genetic analysis workflows. Subsequent WGS of the tumor tissue confirmed biallelic inactivation through the loss of the remaining allele (copy number ≈ 0.86), representing a classic two-hit mechanism. This large-scale deletion of all SDHA exons was further validated using multiplex ligation-dependent probe amplification (MLPA), confirming it as the pathogenic driver. The patient remains under rigorous long-term follow-up given the reported 15% risk of malignancy associated with SDHA variants. Conclusions : This case highlights the clinical utility of WGS in overcoming the inherent limitations of exome-based sequencing for SDHA analysis. When clinical suspicion remains high - specifically in cases with SDHA-negative immunohistochemistry but negative standard genetic testing - WGS or MLPA should be employed to detect hidden structural variants. Accurate molecular diagnosis is essential not only for understanding the mechanism of tumorigenesis but also for tailoring oncological surveillance and genetic counseling for the patient and their family.