Juvenile Polyposis Syndrome, BMPR1A Sequencing and Deletion/Duplication Juvenile polyposis syndrome (JPS) is a genetic disorder that involves the development of multiple juvenile (hamartomatous) polyps in the stomach, small intestine, colon, and rectum. The age of onset varies from childhood to middle age, though most affected Tests to Consider individuals have some polyps by age 20. The risk for gastrointestinal (GI) cancers in JPS families is ~20% by age 35 and approaches ~68% by age 60. Pathogenic variants in the Juvenile Polyposis Syndrome (BMPR1A) BMPR1A or SMAD4 gene are two known molecular causes of JPS, accounting for 28% and Sequencing and Deletion/Duplication 2004992 27% of cases, respectively; at this time, 45% of cases have an unknown etiology. Method: Polymerase Chain Reaction/Sequencing/Multiplex Ligation-dependent Probe Amplication Disease Overview Use to conrm a diagnosis of JPS syndrome in symptomatic individuals. Symptoms/Diagnosis Do not use for presymptomatic or diagnostic testing when a causative BMPR1A variant The diagnosis of JPS is established in a proband with any one of the following: has previously been identied in the family. >5 juvenilea polyps of the colon or rectum Related Tests Multiple juvenile polyps of the upper and lower GI tract Hereditary Hemorrhagic Telangiectasia Any number of juvenile polyps and a family history of juvenile polyposis (HHT) Panel, Sequencing and Identication of a heterozygous pathogenic variant in BMPR1A or SMAD4 gene Deletion/Duplication 2009337 Method: Massively Parallel Sequencing/Exonic Oli- gonucleotide-based CGH Microarray The diagnosis of JPS should be suspected in a proband with the following: May assist in the diagnosis of JPS Anemia, rectal bleeding, or prolapse of rectal polyp Recommended test if clinical suspicion is for >1 juvenile polyp SMAD4 pathogenic variant One or more juvenile polyps and a family history of JPS Familial Mutation, Targeted Sequencing 2001961 aJuvenile refers to the histopathology of the polyp, not the age of onset of polyps. Method: Polymerase Chain Reaction/Sequencing Recommended test when there is a known familial pathogenic sequence variant Genetics previously identied in a family member A copy of the family member’s lab report documenting the familial variant is Genes REQUIRED. BMPR1A , SMAD4 Deletion/Duplication Analysis by MLPA 3003144 Method: Multiplex Ligation-dependent Probe Ampli- Incidence cation 1 ~1/16,000 to 1/100,000 Recommended test when there is a known familial pathogenic deletion/duplication variant previously identied in family member Inheritance A copy of the family member’s lab report documenting the familial variant is Autosomal dominant for JPS REQUIRED. De novo rate: ~67% Penetrance >90% for polyp development Test Interpretation Sensitivity/Specicity Clinical Sensitivity BMPR1A : 28% 2 ,3 ,4 Sequencing variants: 69-85% Deletion/duplication variants: 15% Analytical Sensitivity/Specicity BMPR1A : 99% Results Result Variant detected Interpretation Positive Pathogenic variant detected Conrms a diagnosis of JPS Negative No pathogenic variant detected Does not exclude diagnosis of JPS Uncertain Variant of unknown clinical signicance Unknown if variant is benign or disease causing Limitations A negative result does not exclude a diagnosis of JPS. Diagnostic errors can occur due to rare sequence variations. Interpretation of this test result may be impacted if this individual had an allogeneic stem cell transplantation. The following will not be evaluated: Regulatory region or deep intronic variants Breakpoints of large deletions/duplications Variants in genes other than BMPR1A Large deletions/duplications of exons 7 and 8 in BMPR1A gene may not be detected. The following may not be detected: Some variants due to technical limitations in the presence of pseudogenes, repetitive, or homologous regions Low-level somatic variants References 1. Larsen Haidle J, Howe JR. Juvenile polyposis syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al, eds. GeneReviews, University of Washington; 1993-2021. [Last update: Mar 2017; Accessed: Jul 2021] 2. Aretz S, Stienen D, Uhlhaas S, et al. High proportion of large genomic deletions and a genotype phenotype update in 80 unrelated families with juvenile polyposis syndrome. J Med Genet. 2007;44(11):702-709. 3. Calva-Cerqueira D, Chinnathambi S, Pechman B, et al. The rate of germline mutations and large deletions of SMAD4 and BMPR1A in juvenile polyposis. Clin Genet. 2009;75(1):79-85. 4. van Hattem WA, Brosens LA, de Leng WW, et al. Large genomic deletions of SMAD4, BMPR1A and PTEN in juvenile polyposis. Gut. 2008;57(5):623-627. Additional Resources Ngeow J, Heald B, Rybicki LA, et al. Prevalence of germline PTEN, BMPR1A, SMAD4, STK11, and ENG mutations in patients with moderate-load colorectal polyps. Gastroenterology. 2013;144(7):1402-1409, 1409.e1-5. Related Information Colorectal Cancer Hereditary Gastrointestinal Cancer Panel, Including Lynch Syndrome ARUP Laboratories is a nonprot enterprise of the University of Utah and its Department of Pathology. 500 Chipeta Way, Salt Lake City, UT 84108 (800) 522-2787 | (801) 583-2787 | aruplab.com | arupconsult.com Content Review July 2021 | Last Update August 2021 © 2021 ARUP Laboratories. All Rights Reserved. Client Services - (800) 522-2787.