{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T16:17:25Z","timestamp":1786119445371,"version":"build-2736575974"},"reference-count":47,"publisher":"Oxford University Press (OUP)","issue":"16","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":217,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,7,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Neurodegenerative diseases (NDDs) are clinically and genetically heterogeneous, requiring neuropathology or molecular testing for a definitive diagnosis. Clinical whole genome sequencing (WGS) enables comprehensive variant calling across flexible gene lists that can be tailored to the clinical presentation. By allowing simultaneous detection of single-nucleotide variants, copy-number variants, structural variants, and repeat expansions, WGS has the potential to improve diagnostic yield, facilitate genetic counseling and support clinical trial inclusion. This study assesses the diagnostic performance of WGS in individuals with NDD. WGS in 500 individuals representing a wide spectrum of NDDs identified a disease-causing variant in 61 cases, resulting in a diagnostic yield of 12%. These variants were found in 16 different genes, with C9orf72 being the most prevalent. Repeat expansions represented the largest variant class, accounting for 35 of 61 LP\/P cases (57%); most of which were C9orf72 expansions (31\/35). In the largest phenotype groups, frontotemporal dementia (FTD) had the highest diagnostic yield (19%) followed by amyotrophic lateral sclerosis (ALS, 13%), whereas an underlying monogenic cause was expectedly low in Alzheimer disease (AD, 4%). A positive family history was present in the majority (74%) of FTD, ALS, combined ALS-FTD and AD cases with an LP\/P finding. Clinical WGS provides a clear diagnostic advantage in NDDs marked by substantial clinical and genetic overlap. WGS enables comprehensive variant detection and mapping of genotype\u2013phenotype relationships across the disease continuum. In FTD and ALS, these results support universal access to genetic testing independent of age at onset or family history.<\/jats:p>","DOI":"10.1093\/hmg\/ddag072","type":"journal-article","created":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T11:52:52Z","timestamp":1784807572000},"source":"Crossref","is-referenced-by-count":0,"title":["Clinical genome sequencing in neurodegenerative diseases\u2013outcome in the first 500 patients"],"prefix":"10.1093","volume":"35","author":[{"ORCID":"https:\/\/orcid.org\/0009-0001-6181-7562","authenticated-orcid":false,"given":"Emma","family":"Ehn","sequence":"first","affiliation":[{"name":"Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska Institutet , H1 Neurobiology, Care Sciences and Society, H1 Neurogeriatrics, 171 77 Stockholm,","place":["Sweden"]},{"name":"Karolinska University Hospital Solna, Unit for Hereditary Dementias , Karolinska v\u00e4gen 37A, 171 76 Stockholm,","place":["Sweden"]},{"name":"Karolinska University Hospital Solna, Department of Clinical Genetics and Genomics , Karolinska Universitetslaboratoriet, G\u00e4vlegatan 68, 171 76 Stockholm,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H\u00e5kan","family":"Thonberg","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Department of Clinical Genetics and Genomics , Karolinska Universitetslaboratoriet, G\u00e4vlegatan 68, 171 76 Stockholm,","place":["Sweden"]},{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet , Karolinska University Hospital, Solna (L1:00), 171 76 Stockholm,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Inger","family":"Nennesmo","sequence":"additional","affiliation":[{"name":"Department of Oncology-Pathology , Karolinska Institutet, OnkPat, 171 77 Solna,","place":["Sweden"]},{"name":"Department of Pathology and Cancer Diagnostics, Karolinska University Hospital Solna , Klinisk Patologi\/Cancerdiagnostik, Karolinska Universitetssjukhuset, Solna, 171 76 Solna,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna","family":"Lindstrand","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Department of Clinical Genetics and Genomics , Karolinska Universitetslaboratoriet, G\u00e4vlegatan 68, 171 76 Stockholm,","place":["Sweden"]},{"name":"Department of Molecular Medicine and Surgery, Karolinska Institutet , Karolinska University Hospital, Solna (L1:00), 171 76 Stockholm,","place":["Sweden"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malin","family":"Kvarnung","sequence":"additional","affiliation":[{"name":"Karolinska University Hospital Solna, Department of Clinical Genetics and Genomics , Karolinska Universitetslaboratoriet, G\u00e4vlegatan 68, 171 76 Stockholm,","place":["Sweden"]},{"name":"Department of Molecular 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