High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome

Background

In patients with juvenile polyposis syndrome (JPS) the frequency of large genomic deletions in the SMAD4 and BMPR1A genes was unknown.

Methods

Mutation and phenotype analysis was used in 80 unrelated patients of whom 65 met the clinical criteria for JPS (typical JPS) and 15 were suspected to have JPS.

Results

By direct sequencing of the two genes, point mutations were identified in 30 patients (46% of typical JPS). Using MLPA, large genomic deletions were found in 14% of all patients with typical JPS (six deletions in SMAD4 and three deletions in BMPR1A). Mutation analysis of the PTEN gene in the remaining 41 mutation negative cases uncovered a point mutation in two patients (5%). SMAD4 mutation carriers had a significantly higher frequency of gastric polyposis (73%) than did patients with BMPR1A mutations (8%) (p<0.001); all seven cases of gastric cancer occurred in families with SMAD4 mutations. SMAD4 mutation carriers with gastric polyps were significantly older at gastroscopy than those without (p<0.001). In 22% of the 23 unrelated SMAD4 mutation carriers, hereditary hemorrhagic telangiectasia (HHT) was also diagnosed clinically. The documented histologic findings encompassed a wide distribution of different polyp types, comparable with that described in hereditary mixed polyposis syndromes (HMPS).

Conclusions

Screening for large deletions raised the mutation detection rate to 60% in the 65 patients with typical JPS. A strong genotype‐phenotype correlation for gastric polyposis, gastric cancer, and HHT was identified, which should have implications for counselling and surveillance. Histopathological results in hamartomatous polyposis syndromes must be critically interpreted.Juvenile polyposis syndrome (JPS, OMIM 174900) is an autosomal dominant disorder characterised by the occurrence of multiple juvenile polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon and rectum.^1,2,3 Pathogenic germline mutations in the SMAD4 (MADH4) gene have been identified in around 20% of patients with JPS, and another 20% of patients were found to exhibit a mutation in the BMPR1A gene.^1,4,5,6 A higher frequency of gastric polyposis in carriers of SMAD4 mutations compared with carriers of BMPR1A mutations has been reported.^6,7,8 Most SMAD4 or BMPR1A germline mutations published to date are small insertions/deletions and single base substitutions leading to nonsense, splice‐site or missense mutations (Human Gene Mutation Database). Recently, germline deletions encompassing the contiguous genes BMPR1A and PTEN on chromosome 10q have been reported in five cases of juvenile polyposis of infancy.^9,10 These deletions have been found by absence of parental alleles in the children, quantitative PCR or fluorescence in situ analysis.Large genomic deletions or duplications encompassing ⩾1 exons have been found in several genes using the multiplex ligation‐dependent probe amplification (MLPA) assay.^{11,12,13,14,15} Using the recently developed MLPA test kit for quantitative evaluation of genes involved in JPS, we examined whether large SMAD4 or BMPR1A deletions or duplications are present in patients with JPS with as yet unknown germline mutations, and verified the genotype–phenotype correlation with respect to gastric polyposis.