Mutation screening in juvenile polyposis syndrome.

Juvenile polyposis syndrome (JPS) is an autosomal dominant cancer predisposition syndrome characterized by congenital anomalies, hamartomatous polyps in the gastrointestinal tract, and the development of tumors in these tissues. The diagnosis of JPS is often difficult because of the phenotypic overlap with other hamartomatous polyposis syndromes. Germline mutations have been identified in MADH4 and BMPR1A, aiding in presymptomatic genetic testing. In this study, we describe the results from 3 years of molecular diagnostic screening in JPS. Seventy unrelated individuals referred to our lab for JPS testing were examined through the sequence analysis of coding regions and exon-intron boundaries in both genes. Germline mutations were identified in 30% of cases, with 11.4% in BMPR1A and 18.6% in MADH4. All mutation-positive individuals were negative for cancer at testing, and a single pulmonary valve stenosis was the only congenital anomaly reported. A majority of mutations identified were novel including the first splice site alteration in MADH4. Based on the limited number of exons in each gene, low polymorphism frequency, and high frequency of frameshift or nonsense mutations identified, direct sequence analysis is a suitable methodology for mutation screening if all coding regions and exon-intron boundaries are examined in both genes.