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

Abstract

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.

S3-Leitlinie – Kolorektales Karzinom

“…Die Polypen treten im gesamten Dickdarm auf, KRKs finden sich in über 50 % im rechtsseitigen Kolon und in über 20 % im Rektosigmoid [265]. Aus diesem Grunde muss eine komplette Koloskopie zur Früherkennung durchgeführt werden [256,257,259,260] [380,381]. Daneben ist möglicher-weise das Risiko für Pankreaskarzinome erhöht [382 -386].…”

A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment

“…105 Some individuals with juvenile polyposis syndrome due to mutations in the SMAD4 gene may also have symptoms of hereditary hemorrhagic telangiectasia. 106,107 Referral should be considered for any individual with a personal history of or first-degree relative with (i) three to five cumulative histologically proven juvenile GI polyps [108][109][110] ; (ii) any number of juvenile GI polyps with a positive family history of juvenile polyposis syndrome; or (iii) multiple juvenile polyps located throughout the GI tract.…”

Repository of SMAD4 Mutations: Reference for Genotype/ Phenotype Correlation

“…The majority of missense mutations caused SMAD4 protein charge alterations in exons 10 (Arg361Ser/Gly/Cys/His, Glu330Lys/Gly, Gly352Arg, Cys324Arg and Cys363Arg), 11 (Gly386Asp and Glu390Lys) and 13 (Asp493Ala and Trp509Arg) [7,8,14,15,20,22,[25][26][27][28][29][30]unpublished ARUP data]. The remaining missense mutations from exons 10 and 13 altered the size rather than the charge of the amino acid from the SMAD4 MH2 domain (Tyr353Ser, Leu364Trp, Gly491Val, Gly510Val, Trp524Leu and Leu533Val) [3,7,14,18,20,22,29].…”

“…The majority of missense mutations caused SMAD4 protein charge alterations in exons 10 (Arg361Ser/Gly/Cys/His, Glu330Lys/Gly, Gly352Arg, Cys324Arg and Cys363Arg), 11 (Gly386Asp and Glu390Lys) and 13 (Asp493Ala and Trp509Arg) [7,8,14,15,20,22,[25][26][27][28][29][30]unpublished ARUP data]. The remaining missense mutations from exons 10 and 13 altered the size rather than the charge of the amino acid from the SMAD4 MH2 domain (Tyr353Ser, Leu364Trp, Gly491Val, Gly510Val, Trp524Leu and Leu533Val) [3,7,14,18,20,22,29]. Mutations predicted to lead to a frameshift and eventually cause the formation of a premature stop codon were found in exon 10 (4 deletions and 1 insertion), exon 11 (3 deletions), exon 12 (4 deletions and 1 insertion) and exon 13 (3 deletions, 2 insertions and 2 duplications) [3,4,7,8,14,[16][17][18][19][20][21][22]26,28,30,unpublished ARUP results].…”

“…This combined syndrome of juvenile polyposis and HHT (JP/HHT; MIM 175050) is characterized by symptoms of both diseases in different family members in the same family or as the presence of both JPS and HHT in an affected individual [12,13]. One previous study found that 22% of individuals with a SMAD4 mutation in their JPS population also had HHT [14]. But this percentage is likely higher since JPS patients have not historically *Corresponding author: Pınar Bayrak-Toydemir, M.D., Ph.D., Department of Pathology University of Utah, ARUP Laboratories, 500 Chipeta Way, Salt Lake City, UT 84108, Tel : 801-583-2787 x13171; Fax : 801-584-5207; E-mail: pinar.bayraktoydemir@aruplab.com been well evaluated for HHT manifestations and visa versa.…”