Rothmund-Thomson syndrome due toRECQ4 helicase mutations: Report and clinical and molecular comparisons with Bloom syndrome and Werner syndrome

Abstract

Rothmund‐Thomson syndrome (RTS), an autosomal recessive disorder, comprises poikiloderma, growth deficiency, some aspects of premature aging, and a predisposition to malignancy, especially osteogenic sarcomas. Two kindreds with RTS were recently shown to segregate for mutations in the human RECQL4 helicase gene. We report identification of a new RTS kindred in which both brothers developed osteosarcomas. Mutation analysis of the RECQL4 gene was performed on both brothers and both parents. The brothers were shown to be compound heterozygotes for mutations in the RECQL4 gene, including a single base‐pair 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‐exon boundary of exon 8, which would be predicted to cause a deletion of at least part of a consensus helicase domain. Each parent was shown to be a heterozygote carrier for one mutation. This report strengthens the association between mutations in RECQL4 helicase gene and RTS. Two other recessive disorders, Bloom syndrome and Werner syndrome, are known to be due to other human RECQ helicase gene mutations. These three disorders all manifest abnormal growth, premature aging, and predisposition to site‐specific malignancies. The clinical and molecular aspects of RTS, Bloom syndrome, and Werner syndrome are compared and contrasted. Am. J. Med. Genet. 90:223–228, 2000.