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Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, <jats:italic>SMARCB1<\/jats:italic>, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving <jats:italic>SMARCB1<\/jats:italic> in RMC remains limited.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Methods<\/jats:title>\n                <jats:p>We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children\u2019s Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the <jats:italic>HBB<\/jats:italic> locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of <jats:italic>SMARCB1<\/jats:italic> and integrated RNA sequencing to interrogate the structural variants at the <jats:italic>SMARCB1<\/jats:italic> locus.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Results<\/jats:title>\n                <jats:p>We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the <jats:italic>HBB<\/jats:italic> locus identified the sickle cell mutation as the sole candidate variant. We further identify that the <jats:italic>SMARCB1<\/jats:italic> structural variants are characterized by blunt or 1-bp homology events.<\/jats:p>\n              <\/jats:sec><jats:sec>\n                <jats:title>Conclusions<\/jats:title>\n                <jats:p>Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt <jats:italic>SMARCB1<\/jats:italic> function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.<\/jats:p>\n              <\/jats:sec>","DOI":"10.1186\/s13073-021-00929-4","type":"journal-article","created":{"date-parts":[[2021,7,14]],"date-time":"2021-07-14T19:03:52Z","timestamp":1626289432000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Haplotype-resolved germline and somatic alterations in renal medullary carcinomas"],"prefix":"10.1186","volume":"13","author":[{"given":"Kar-Tong","family":"Tan","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyunji","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Carrot-Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuxiang","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Won Jun","family":"Kim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guillaume","family":"Kugener","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeremiah A.","family":"Wala","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas P.","family":"Howard","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yueh-Yun","family":"Chi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rameen","family":"Beroukhim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Heng","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gavin","family":"Ha","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Seth L.","family":"Alper","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth J.","family":"Perlman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth A.","family":"Mullen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William C.","family":"Hahn","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthew","family":"Meyerson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrew L.","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,7,14]]},"reference":[{"key":"929_CR1","doi-asserted-by":"publisher","unstructured":"Ezekian B, Englum B, Gilmore BF, Nag UP, Kim J, Leraas HJ, Routh JC, Rice HE, Tracy ET (2017) Renal medullary carcinoma: a national analysis of 159 patients. 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