Germline whole exome sequencing implicates homologous recombination repair pathway genes as risk factors in SMARCB1 deficient renal medullary phenotypes without sickle hemoglobinopathies

Renal medullary carcinoma (RMC) is a highly aggressive, SMARCB1-deficient kidney cancer classically arising in young individuals of African descent with sickle hemoglobinopathies, most commonly sickle cell trait, due to germline HBB variants. Very rare SMARCB1-deficient cases without sickle hemoglobinopathies are classified as renal cell carcinoma, unclassified with medullary phenotype (RCCU-MP). Apart from confirming sickle hemoglobinopathies, there is no established role for germline testing in RMC or RCCU-MP, and germline risk factors for RCCU-MP remain undefined. We performed an integrated germline whole-exome sequencing (WES) and bulk RNA sequencing (RNA-Seq) on 11 patients with RCCU-MP and compared them with 23 patients with canonical RMC associated with sickle hemoglobinopathies (sickle cell trait, n=22; sickle cell-C disease, n=1) and with disease-control cohorts of clear cell RCC (ccRCC; n=11) and chromophobe RCC (chRCC; n=11). RCCU-MP harbored pathogenic germline loss-of-function protein-truncating variants (PTVs) in homologous recombination repair (HRR) pathway genes in 2 of 11 cases (~18%): ATM (W2960*, affecting the PIKKc_ATM domain) and RAD50 (E696*, affecting the Rad50_zn_hook domain). No germline pathogenic HRR pathway PTVs were found in RMC, ccRCC, or chRCC. Furthermore, aside from the expected HBB variants defining sickle hemoglobinopathies in the RMC cohort, no additional germline alterations associated with other hemoglobinopathies - including alpha-thalassemia and alpha/beta-hemoglobinopathies ( KLF1, ATRX, HBG1, HBS1L, MYB, HBD, HBA1, HBA2, HBG2, HBZ and BCL11A ) - were detected in any specific cohort. RNA-Seq cellular deconvolution techniques such as ssGSEA tumor micro-environment (TME) reconstruction and Kassandra cellular deconvolution showed microenvironment with high enrichment for B cells, CD4 and CD8 T cells, and low presence of endothelial cells in both RMC and RCCU-MP cases. These data represent, to our knowledge, the largest germline analysis to date spanning both RMC and RCCU-MP and nominate HRR pathway disruption as a potential germline susceptibility signal specifically for RCCU-MP. Defining HRR-linked germline risk in RCCU-MP refines patient selection for genetic counseling and lays the groundwork for mechanistic and therapeutic studies in SMARCB1-deficient medullary kidney cancers beyond sickle hemoglobinopathies. The ChatGPT-5.1 was used to improve readability and language, and after using this tool, the content was reviewed and edited as needed.