Rothmund-Thomson syndrome due to RECQ4 helicase mutations: Report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome

Rothmund-Thomson syndrome (RTS), an autosomal recessive disorder, comprises poikiloderma, growth deficiency, some aspects of premature aging, and a pr edisposition to malignancy, especially osteogenic sarcomas, Two kindreds wi th RTS were recently shown to segregate for mutations in the human RECQL4 h elicase gene. We report identification of a new RTS kindred in which both b rothers developed osteosarcomas, Mutation analysis of the RECQL4 gene was p erformed on both brothers and both parents. The brothers were shown to be c ompound heterozygotes for mutations in the RECQL4 gene, including a single basepair deletion in exon 9 resulting in a frameshift and early termination codon and a base substitution in the 3-prime splice site in the intron-exo n boundary of exon 8, which would be predicted to cause a deletion of at le ast part of a consensus helicase domain. Each parent was shown to be a hete rozygote carrier for one mutation. This report strengthens the association between mutations in RECQL4 helicase gene and RTS, Two other recessive diso rders, Bloom syndrome and Werner syndrome, are known to be due to other hum an RECQL4 helicase gene mutations. These three disorders all manifest abnor mal growth, premature aging, and predisposition to site-specific malignanci es. The clinical and molecular aspects of RTS, Bloom syndrome, and Werner s yndrome are compared and contrasted. (C) 2000 Wiley-Liss, Inc.