Haplotype association and mutation analysis of the transglutaminase 1 gene for prenatal exclusion of lamellar ichthyosis.

Lamellar ichthyosis (LI) is an autosomal recessive keratinization disorder of the skin. Genetic heterogeneity has been shown for the disease and there is evidence for the involvement of the transglutaminase 1 (TGM1) gene on chromosome 14q11. We have previously identified chromosome 14q11 haplotypes associated with ichthyosis in the Norwegian population. In this paper we describe antenatal exclusion of ichthyosis in two Norwegian families by chromosome 14q11 haplotype association and direct mutation analysis. In one pregnancy, the 11-week old fetus at risk for LI was found to share only one disease-associated haplotype. A subsequent mutation analysis of the TGM1 gene in fetal DNA revealed that the fetus carried a novel 3795A-->T transversion. The affected proband was compound heterozygous for the mutations 3795A-->T and 3239G-->C resulting in an Asp430Val and a Val379Leu, respectively. In another LI family, the 11-week old fetus was found to be heterozygous for the 14q11 haplotype associated with the disease. Subsequent mutation analysis revealed that the fetus was heterozygous for the 2526A-->G transition in the splice site of intron 5 whereas the proband was homozygous for the same mutation. Our results show that haplotyping can be a useful tool for prenatal diagnosis in diseases with genetic heterogeneity.