Linkage study of a large Danish 4-generation family with urge incontinence and nocturnal enuresis.

OBJECTIVE

We studied a large 4-generation family in which night and day voiding problems segregated in an autosomal dominant pattern with a high penetrance. We mapped the gene(s) causing these forms of incontinence using a total genome scan approach.

METHODS

The family comprises 74 subjects in 4 generations. The clinical phenotypes were evaluated by detailed questionnaires and frequency volume charts. Genetically, a genome scan approach with 500 polymorphic marker systems was used to localize a chromosome area for the trait(s) and to narrow down a candidate region. The 3 different genetic models studied were 1) a single gene causing either day, night or day and night incontinence; 2) a gene primarily causing night incontinence; and 3) 2 different genes each causing only day or night incontinence.

RESULTS

For model 2 we found 2 areas that gave a high lod score on 2-point analysis (D4S2960, 4p16.1, Z = 3.66 and D12S86, 12q24.2, Z = 3.22) on chromosome 4p and 12q. With an estimated penetrance of 75% only 4p linkage was significant. Models 1 and 3 were excluded as causes due to lack of the affected haplotype in affected subjects. Based on manual haplotype and 2-point analyses, all other areas were excluded for linkage.

CONCLUSIONS

The most likely genetic model in this kindred seems to be a gene located on chromosome 4p16.1 causing primarily nocturnal enuresis. However, involvement of chromosome 12q24.3 cannot be excluded for linkage. The dopamine receptors DRD5 and D1B are mapped to chromosome 4p16. These genes are candidate genes for nocturnal enuresis and urge incontinence.