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To understand the genetic basis of neurological resilience, we analyzed an NPC family with variable phenotypes, identifying loss\u2010of\u2010function variants in\n                    <jats:italic>CCDC115<\/jats:italic>\n                    ,\n                    <jats:italic>SLC4A5<\/jats:italic>\n                    ,\n                    <jats:italic>DEPDC5<\/jats:italic>\n                    ,\n                    <jats:italic>ETFDH<\/jats:italic>\n                    ,\n                    <jats:italic>SNRNP200<\/jats:italic>\n                    , and\n                    <jats:italic>DOCK1<\/jats:italic>\n                    that co\u2010segregated with milder neurological involvement. Using yeast models, we successfully predicted NPC\u2010like severity based on orthologous gene variants. RNA\u2010seq revealed a positive correlation between mitochondrial transcripts and cellular fitness. Modeling NPC in yeast lacking the\n                    <jats:italic>SLC4A5<\/jats:italic>\n                    ortholog,\n                    <jats:italic>bor1<\/jats:italic>\n                    , enhanced cellular fitness, improved mitochondrial function, and reduced sterol accumulation. Our findings identify potential modifiers and biomarkers of NPC severity, highlighting mitochondrial pathways and\n                    <jats:italic>SLC4A5<\/jats:italic>\n                    as a therapeutic target.\n                  <\/jats:p>\n                  <jats:p>\n                    <jats:boxed-text content-type=\"box\" position=\"anchor\">\n                      <jats:caption>\n                        <jats:title>Impact statement<\/jats:title>\n                      <\/jats:caption>\n                      <jats:p>Niemann\u2010Pick type C (NPC) disease is a progressive neurovisceral lysosomal storage disorder. Here, we identified genomic modifiers of neurological resilience in an NPC family, with SLC4A5 emerging as a key biomarker and therapeutic target. Additionally, our study highlighted mitochondrial transcripts and metabolites as potential biomarkers of severity.<\/jats:p>\n                    <\/jats:boxed-text>\n                  <\/jats:p>","DOI":"10.1002\/1873-3468.70091","type":"journal-article","created":{"date-parts":[[2025,6,12]],"date-time":"2025-06-12T13:24:38Z","timestamp":1749734678000},"page":"2582-2597","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Genomic modifiers of neurological resilience in a Niemann\u2010Pick C family"],"prefix":"10.1002","volume":"599","author":[{"given":"Macarena","family":"Las Heras","sequence":"first","affiliation":[{"name":"Facultad de Medicina, Centro de Gen\u00e9tica y Gen\u00f3mica Cl\u00ednica Alemana Universidad del Desarrollo  Santiago Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjam\u00edn","family":"Szenfeld","sequence":"additional","affiliation":[{"name":"Facultad de Medicina, 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