Abstract
Primary focal hyperhidrosis (PFH, OMIM %144110) is a genetically influenced condition characterised by excessive sweating. Prevalence varies between 1.0–6.1% 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.
Highlights
Primary focal hyperhidrosis (PFH, OMIM %144110) is a relatively common, yet poorly understood disorder
Within our sample of nine selected families, 51 out of 112 individuals were affected by PFH, 57 were non-affected and for four subjects the affection status could not be determined as selfreports and questionnaire data deferred
Primary focal hyperhidrosis, which is characterised by excessive perspiration of the eccrine sweat glands in palms, soles, and axillae is a heritable disorder
Summary
Primary focal hyperhidrosis (PFH, OMIM %144110) is a relatively common, yet poorly understood disorder. Only two groups have reported genetic linkage studies, resulting in different chromosomal loci. Higashimoto and colleagues investigated eleven families (42 affected, 40 non-affected subjects) using genome-wide polymorphic markers to identify a disease locus [8]. Chen and colleagues established genetic linkage in a six-generation family (11 affected, 10 non-affected subjects) from South East China affected by PFH on chromosome 2q22.1-2q31.1 [9]. The locus they describe consists of a 31.26 Mega base pair (Mbp) region of weaker linkage (LOD score 0.772–1.142) between rs12999055 and rs4668136, and a 4.59 Mbp region of significant linkage (LOD score 2.24–3.03) between rs2683451 and rs643346. We found four significant loci, one of them overlapping with the chromosomal region on chromosome 2q22.1-2q31.1 reported previously by Chen and colleagues [9]
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