Prenatal exclusion of lamellar ichthyosis based on identification of two new mutations in the transglutaminase 1 gene.

Lamellar ichthyosis is a severe, generalized, autosomal recessive genodermatosis characterized clinically by large, parchment-like scales and histologically by acanthosis and marked hyperkeratosis. Genetic heterogeneity in lamellar ichthyosis has been recognized with reports of two linked loci (on chromosomes 14q11 and 2q33-35). In a cohort of four small families with lamellar ichthyosis we found confirmatory evidence for linkage (p < or = 0.01) to D14S275, a microsatellite marker close to transglutaminase 1 on chromosome 14q11. We also identified two novel transglutaminase 1 mutations in an affected sibling pair from one of these families. The paternal mutation in exon 3, 1387insCAGC, causes a frameshift predicted to result in premature termination of translation within the same exon. The maternal mutation in exon 8, 4561delAC, also causes a frameshift and a premature stop codon in this exon. The mother of these siblings recently became pregnant with twins. Genotyping and direct sequencing of DNA isolated from fetal amniotic fluid cultures revealed the presence of the paternal but the absence of the maternal mutation, thus predicting a normal skin phenotype. Both twins were born with normal-appearing skin. Our findings demonstrate that mutations of both alleles of the transglutaminase 1 gene are the cause of lamellar ichthyosis in this family, and illustrate an emerging clinical application of molecular genetics in dermatology.