Welcome to the Gene Scene! Each week, we will explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. Here, we focus on the condition that led to the gene’s inclusion on the list, providing clear, relevant information that supports your clinic. To subscribe to the Gene Scene, contact your local GSL or send a request to info@ambrygen.com. 

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Clinical Phenotype Summary: 

The BMPR1A gene (NM_004329.2) is located on chromosome 10q23.2, encodes the bone morphogenetic protein receptor type-1A protein, and contains 11 coding exons. Pathogenic variants in this gene are known to cause juvenile polyposis syndrome (JPS), which is inherited in an autosomal dominant fashion. 

Juvenile Polyposis Syndrome (JPS) is characterized by:
•    Development of multiple hamartomatous "juvenile" polyps in the gastrointestinal tract, most commonly in the colon, but also in the stomach and small intestine.

Hamartomatous polyps can lead to chronic GI bleeding, iron-deficiency anemia, abdominal pain, diarrhea, and intussusception. 

Pathogenic variants in BMPR1A confer a significantly increased risk for colon cancer (up to 50% lifetime risk); gastric cancer is rarely reported in individuals with BMPR1A-related JPS.

The penetrance of BMPR1A-related JPS is incomplete, and variable expressivity is observed; therefore, cancer risks will differ based on individual and family history. Loss of function has been reported as the mechanism of disease for BMPR1A-related JPS.

Unique Considerations: 

•    The term ‘Juvenile’ does not refer to the age of the patient, but rather to the type of tissue (hamartomatous tissue) that is found in the polyp

•    It is estimated that more than 50% of cases of JPS cases occur de novo

Clinical Resources: 
•    Clinician Management Resource: Juvenile Polyposis Syndrome (BMPR1A) 

Citations: 
•    ‘Occurrence of gastric cancer in patients with juvenile polyposis syndrome: a systematic review and meta-analysis’ Gastrointestinal endoscopy 2023 Mar; 97(3):407-414.e1 (Singh AD,Gupta A,Mehta N,Heald B,Macaron C,Liska D,Bhatt A,Burke CA) PMID: 36265529.
•    ‘Phenotypic Differences in Juvenile Polyposis Syndrome With or Without a Disease-causing SMAD4/BMPR1A Variant.’ Cancer prevention research (Philadelphia, Pa.) 2021 02; 14(2):215-222 (MacFarland SP,Ebrahimzadeh JE,Zelley K,Begum L,Bass LM,Brand RE,Dudley B,Fishman DS,Ganzak A,Karloski E,Latham A,Llor X,Plon S,Riordan MK,Scollon SR,Stadler ZK,Syngal S,Ukaegbu C,Weiss JM,Yurgelun MB,Brodeur GM,Mamula P,Katona BW) PMID: 33097490
•    Ishida H, Ishibashi K, Iwama T. Malignant tumors associated with juvenile polyposis syndrome in Japan. Surg Today. 2018 Mar;48(3):253-263. doi: 10.1007/s00595-017-1538-2. Epub 2017 May 26. PMID: 28550623.
•    Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW; American College of Gastroenterology. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. Am J Gastroenterol. 2015 Feb;110(2):223-62; quiz 263. doi: 10.1038/ajg.2014.435. Epub 2015 Feb 3. PMID: 25645574
•    Friedl W, Uhlhaas S, Schulmann K, Stolte M, Loff S, Back W, Mangold E, Stern M, Knaebel HP, Sutter C, Weber RG, Pistorius S, Burger B, Propping P. Juvenile polyposis: massive gastric polyposis is more common in MADH4 mutation carriers than in BMPR1A mutation carriers. Hum Genet. 2002 Jul;111(1):108-11. doi: 10.1007/s00439-002-0748-9. Epub 2002 Jun 13. PMID: 12136244.
 
Ambry Genetics Gene-Disease Validity Scheme
Each week, we explore a gene from the ACMG Secondary Findings list—genes identified by the American College of Medical Genetics and Genomics as having clear, actionable health implications. These genes are included because they’re linked to serious but preventable or manageable conditions when identified early. 

To learn more about the ACMG Secondary Findings list, click here.

To read all previous Gene Scene emails, click here.