{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,9]],"date-time":"2026-01-09T15:30:10Z","timestamp":1767972610893,"version":"3.49.0"},"reference-count":48,"publisher":"Public Library of Science (PLoS)","issue":"12","license":[{"start":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T00:00:00Z","timestamp":1609286400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Primary focal hyperhidrosis (PFH, OMIM %144110) is a genetically influenced condition characterised by excessive sweating. Prevalence varies between 1.0\u20136.1% in the general population, dependent on ethnicity. The aetiology of PFH remains unclear but an autosomal dominant mode of inheritance, incomplete penetrance and variable phenotypes have been reported. In our study, nine pedigrees (50 affected, 53 non-affected individuals) were included. Clinical characterisation was performed at the German Hyperhidrosis Centre, Munich, by using physiological and psychological questionnaires. Genome-wide parametric linkage analysis with GeneHunter was performed based on the Illumina genome-wide SNP arrays. Haplotypes were constructed using easyLINKAGE and visualised via HaploPainter. Whole-exome sequencing (WES) with 100x coverage in 31 selected members (24 affected, 7 non-affected) from our pedigrees was achieved by next generation sequencing. We identified four genome-wide significant loci, 1q41-1q42.3, 2p14-2p13.3, 2q21.2-2q23.3 and 15q26.3-15q26.3 for PFH. Three pedigrees map to a shared locus at 2q21.2-2q23.3, with a genome-wide significant LOD score of 3.45. The chromosomal region identified here overlaps with a locus at chromosome 2q22.1-2q31.1 reported previously. Three families support 1q41-1q42.3 (LOD = 3.69), two families share a region identical by descent at 2p14-2p13.3 (LOD = 3.15) and another two families at 15q26.3 (LOD = 3.01). Thus, our results point to considerable genetic heterogeneity. WES did not reveal any causative variants, suggesting that variants or mutations located outside the coding regions might be involved in the molecular pathogenesis of PFH. We suggest a strategy based on whole-genome or targeted next generation sequencing to identify causative genes or variants for PFH.<\/jats:p>","DOI":"10.1371\/journal.pone.0244565","type":"journal-article","created":{"date-parts":[[2020,12,30]],"date-time":"2020-12-30T19:14:50Z","timestamp":1609355690000},"page":"e0244565","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":12,"title":["Genome-wide linkage analysis of families with primary hyperhidrosis"],"prefix":"10.1371","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9581-516X","authenticated-orcid":true,"given":"Andrea 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Japanese females identifies fifteen novel skin-related trait associations","volume":"8","author":"C Endo","year":"2018","journal-title":"Sci Rep"},{"key":"pone.0244565.ref033","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1046\/j.1365-2133.2002.05059.x","article-title":"Effect of botulinum toxin type A on quality of life measures in patients with excessive axillary sweating: a randomized controlled trial","volume":"147","author":"MK Naumann","year":"2002","journal-title":"British Journal of Dermatology"},{"key":"pone.0244565.ref034","doi-asserted-by":"crossref","first-page":"P51","DOI":"10.1016\/j.jaad.2003.10.202","article-title":"Validity and reliability of the hyperhidrosis disease severity scale (HDSS)","volume":"50","author":"JW Kowalski","year":"2004","journal-title":"J Am Acad Dermatol"},{"key":"pone.0244565.ref035","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1111\/j.1087-0024.2004.09113.x","article-title":"10 years experience of the Dermatology Life 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Auton","year":"2015","journal-title":"Nature"},{"key":"pone.0244565.ref039","doi-asserted-by":"crossref","first-page":"789","DOI":"10.1038\/nature02168","article-title":"The International HapMap Project","volume":"426","author":"RA Gibbs","year":"2003","journal-title":"Nature"},{"key":"pone.0244565.ref040","first-page":"1323","article-title":"Descent graphs in pedigree analysis: applications to haplotyping, location scores, and marker-sharing statistics","volume":"58","author":"E Sobel","year":"1996","journal-title":"Am J Hum Genet"},{"key":"pone.0244565.ref041","first-page":"1347","article-title":"Parametric and nonparametric linkage analysis: a unified multipoint approach","volume":"58","author":"L Kruglyak","year":"1996","journal-title":"Am J Hum Genet"},{"key":"pone.0244565.ref042","doi-asserted-by":"crossref","first-page":"3565","DOI":"10.1093\/bioinformatics\/bti571","article-title":"easyLINKAGE-Plus\u2014automated linkage analyses using large-scale SNP 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