Variable Features of Juvenile Polyposis Syndrome With Gastric Involvement Among Patients With a Large Genomic Deletion of BMPR1A

Abstract

OBJECTIVES: Loss-of-function mutations of BMPR1A cause juvenile polyposis syndrome (JPS), but large genomic deletions in BMPR1A are rare, reported in few families only, and data regarding the associated phenotype are limited. METHODS: We investigated clinical features and genomic data of 7 extended seemingly unrelated families with a genomic deletion of the entire coding region of BMPR1A . We defined mutation size, mutation prevalence, and tumor pathogenesis using whole-genome sequencing, targeted genotyping, and haplotype analysis. RESULTS: Patients with JPS from 7 families of Bukharin Jewish ancestry carried a deletion of 429 kb, encompassing the BMPR1A coding sequence and 8 downstream genes. Haplotype analysis and testing controls identified this as a common founder mutation occurring in 1/124 individuals of Bukharin origin. Tumor testing did not demonstrate loss of heterozygosity. Among carriers, JPS was almost fully penetrant, but clinical features varied widely, ranging from mild to very severe, including pan-enteric polyps, gastritis, and colorectal, esophageal, and testicular cancer, and carriers with phenotypes, which would not have raised suspicion of JPS. DISCUSSION: The phenotype in this large cohort was extremely variable, although all carriers shared the same variant and the same genetic background. New observations include a preponderance of adenomatous rather than juvenile polyps, possible association with testicular cancer, and unexpected upper gastrointestinal involvement.

Whole Genome Sequencing Applied in Familial Hamartomatous Polyposis Identifies Novel Structural Variations

“…Whole-genome sequencing (WGS) has recently emerged as an excellent diagnostic tool for infrequent diseases, enabling identification of genomic mutations and SVs or CNVs such as large deletions, duplications and inversions. Indeed, large genomic deletions in SMAD4 and BMPR1A can explain JPS [ 7 , 8 , 9 , 10 , 11 ]. WGS is not sensitive to an enrichment kit; therefore, it results in high-quality variant calling [ 6 ].…”

Phenotypic diversity among juvenile polyposis syndrome patients from different ethnic background

“…Among BMPR1A mutation carriers, seven families were from NRFSU, specifically from Bukhara (a city in Uzbekistan). The Bukharin Jewish families originate from a highly endogamous community in central Asia for some 2500 years, and immigrated to Israel after the collapse of the former Soviet Union [ 25 ]. These seven families carry a founder mutation comprising a large genomic deletion of 429,426 bp (chr10:88,611,882- 89,041,308 [hg19]), encompassing the entire coding region (exons 3–13) of BMPR1A , and the complete loci of 8 downstream genes [ 25 ].…”

“…The Bukharin Jewish families originate from a highly endogamous community in central Asia for some 2500 years, and immigrated to Israel after the collapse of the former Soviet Union [ 25 ]. These seven families carry a founder mutation comprising a large genomic deletion of 429,426 bp (chr10:88,611,882- 89,041,308 [hg19]), encompassing the entire coding region (exons 3–13) of BMPR1A , and the complete loci of 8 downstream genes [ 25 ]. Having a mutation in general, having a mutation in either gene or having a specific mutation (i.e.the BMPR1A Bukharin mutation) was not associated with any specific phenotype or with disease severity compared to participants who had negative genetic results (no mutation identified) or have not been tested, had a mutation in the other gene (BMPR1A or SMAD4 ) or had a non- BMPR1A Bukharin mutation, respectively.…”

Updates in the field of hereditary nonpolyposis colorectal cancer

“…Furthermore, the seemingly different phenotypes may overlap. For example, Lieberman et al [111] evaluated seven unrelated families sharing a genomic deletion of the entire coding region of BMPR1A and found extremely variable phenotypes despite the same predisposing mutation and the same genetic background (Bukharin Jewish ancestry). Importantly, adenomatous polyps predominated over juvenile polyps in the families [111].…”

“…For example, Lieberman et al [111] evaluated seven unrelated families sharing a genomic deletion of the entire coding region of BMPR1A and found extremely variable phenotypes despite the same predisposing mutation and the same genetic background (Bukharin Jewish ancestry). Importantly, adenomatous polyps predominated over juvenile polyps in the families [111]. Lastly, Evans et al [112] conducted a targeted investigation on 22 unrelated FCCTX families from Newfoundland to determine the frequency of BMPR1A germline mutations: no rare (mutant allele frequency < 1%) or novel variants were found.…”