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Although more than 80 genes have been associated with HSP, achieving definite genetic diagnosis remains challenging, limiting effective patient care, genetic counseling, and understanding of genotype\u2013phenotype correlations. This study aimed to investigate the diagnostic yield of clinical exome sequencing (CES) in a cohort of Spanish individuals with suspected HSP and to explore genotype\u2013phenotype correlations.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A total of 139 non\u2010related Spanish individuals with HSP underwent standardized clinical evaluation and CES. Genetic analyses were performed using a virtual panel containing 129 HSP\u2010associated genes, complemented by phenotype\u2010driven filtering through the Human Phenotype Ontology. Statistical analyses were performed on core clinical and paraclinical features.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      After clinical review, 108 index cases were included. Male patients were slightly more represented and mean age at onset was 33\u2009years. Pure HSP forms were more prevalent. The most frequent presenting symptoms were gait disturbance and recurrent falls. A genetic diagnosis was achieved in 57 patients (52,8%), with\n                      <jats:italic>SPAST<\/jats:italic>\n                      and\n                      <jats:italic>SPG7<\/jats:italic>\n                      being the most frequently mutated genes. In total, pathogenic\/likely pathogenic variants were identified across 21 genes, including 8 novel variants. HSP with autosomal recessive inheritance was more common than autosomal dominant (29 vs. 25 cases), while dominant\/recessive X\u2010linked disease forms were rare (3 cases).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>CES combined with HPO\u2010based filtering is an effective strategy for achieving genetic diagnosis in patients with suspicion of HSP.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/ene.70475","type":"journal-article","created":{"date-parts":[[2026,1,21]],"date-time":"2026-01-21T06:32:06Z","timestamp":1768977126000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Diagnostic Yield and Genotype\u2013Phenotype Correlations of Clinical Exome Sequencing in Hereditary Spastic Paraparesis: Experience From Eastern Spain"],"prefix":"10.1111","volume":"33","author":[{"given":"Lid\u00f3n","family":"Carretero\u2010Vilarroig","sequence":"first","affiliation":[{"name":"Cellular, Molecular and Genomics Biomedicine Group La Fe Health Research Institute  Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rafael","family":"Sivera","sequence":"additional","affiliation":[{"name":"Neuromuscular Diseases Unit, Neurology Department La Fe University and Polytechnic Hospital  Valencia Spain"},{"name":"Center for Biomedical Network Research on Rare Diseases (CIBERER) Instituto de Salud Carlos III  Madrid Spain"},{"name":"European Reference Network for Rare Neuromuscular Diseases (ERN EURO\u2010NMD)  Valencia Spain"},{"name":"Medicine Department Universidad CEU\u2010Cardenal Herrera  Valencia Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Raquel","family":"Baviera","sequence":"additional","affiliation":[{"name":"Cellular, Molecular and Genomics Biomedicine Group 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