An immune defect causing dominant chronic mucocutaneous candidiasis and thyroid disease maps to chromosome 2p in a single family

Abstract

We describe a large family in which a combination of chronic mucocutaneous candidiasis (fungal infections of the skin, nails, and mucous membranes) and thyroid disease segregate as an autosomal dominant trait with reduced penetrance. The family includes (a) four members with both candidiasis and thyroid disease, (b) five members, including one pair of phenotype-concordant MZ twins, with candidiasis only, and (c) three members with thyroid disease only. A whole-genome scan using DNA samples from 20 members of the family identified a candidate linkage region on chromosome 2p. By sampling additional individuals and genotyping supplementary markers, we established linkage to a region of approximately 15 cM bounded by D2S367 and D2S2240 and including seven adjacent markers consistent with linkage. With a penetrance estimate of.8, which was based on pedigree and affected status, the peak two-point LOD score was 3.70 with marker D2S2328, and the peak three-point LOD score was 3.82. This is the first linkage assignment of a dominant locus for mucocutaneous candidiasis.

Figures

Figure 1

Partial pedigree segregating CMC (symbols with right half blackened) and thyroid disease (symbols with left half blackened), showing subjects contributing DNA for both phases of analysis (black dots above symbols) or for fine mapping only (white dots above symbols). Individuals for whom CMC was unknown are denoted by symbols enclosed within square brackets. Generation V (not shown) contained four children who were too young for phenotype assignment but whose DNA was genotyped. There was anecdotal evidence that one or more spouses of III-5 were related to individuals in generation II, but we were unable to confirm the relationship(s). Therefore, the father of twins IV-2 and IV-3, the father of IV-4, and the father of IV-5 were designated as unaffected, ungenotyped men with a low likelihood of carrying the disease allele.

Figure 2

Candida infection of the skin and nails in subjects IV-7 (left) and III-8 (right)