Purpose

Background: Autoimmune and cardiovascular diseases are diagnostically complex, especially when multiple rare disorders co-occur in a single patient. This study presents a comprehensive genomic analysis of a 50-year-old female patient with mixed ancestry and a history of thrombotic thrombocytopenic purpura (TTP), systemic lupus erythematosus (SLE), and left ventricular non-compaction cardiomyopathy (LVNC).

Methods: Whole genome sequencing (WGS) data was analyzed, and followed by a tiered variant prioritization strategy using the SEQ platform. A symptom-guided filtering approach was applied using Human Phenotype Ontology (HPO) terms associated with each of the patient’s conditions. Additional layers of interpretation included ACMG classification, minor allele frequency thresholds, and pathway enrichment analysis via g:Profiler.

Results: Out of 5.9 million single nucleotide variants (SNVs), 209 of them passed initial filtering based on tier-based classification and population allele frequency (<1%). Furthermore, 42 candidate variants across 25 genes met ACMG criteria (excluding benign categories) and HPO-based phenotype filters aligned with the patient’s symptoms. Several variants were classified as VUS, yet mapped to symptom-relevant genes such as DOCK11, C4A, C4B, ADA2, and DNASE1, indicating potential modifier or overlapping effects between SLE and TTP. Notably, TTN, RPL3L, and GET3 variants aligned with the patient’s cardiac features, while HLA gene variants appeared relevant to her autoimmune and thrombotic manifestations. SV overlaps across SLE, TTP, and LVNC are consistent with convergent mechanisms but lack statistical validation in this single patient case.

Conclusion: This study demonstrates feasibility of a symptom-to-variant filtering strategy to generate phenotype-aligned candidate variants in a diagnostically challenging case. While many of the identified variants are classified as VUS, the integrated analysis of SNVs, SVs, and functional enrichment highlights candidate genes for further investigation. The findings support a polygenic or synergistic model underlying the patient’s complex presentation, requiring follow-up validation and testing across broad cohort studies.

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