Abstract
BACKGROUND: Pathogenic variants of the bone morphogenetic protein receptor type 1 A (BMPR1A) gene underlie juvenile polyposis syndrome (JPS), a rare autosomal dominant condition characterized by multiple gastrointestinal hamartomatous polyps. Recent findings indicate that constitutional BMPR1A variants can also be associated with various non-JPS phenotypes without hamartomatous polyps. The basis of varying genotype - phenotype relationships is poorly understood. METHODS: We investigated four families with non-truncating variants of BMPR1A affecting different functional domains. Clinical presentation resembled familial colorectal cancer type X-like syndrome with dominantly inherited microsatellite-stable gastrointestinal adenomas and carcinomas. To gain insights into genotype-phenotype associations, exome sequencing was conducted on normal and tumor tissue DNAs. Constitutional BMPR1A variants underwent a thorough evaluation for clinical significance, by, e.g., co-segregation analyses and in silico modeling, supplemented by haplotyping and genealogical studies. All available tumors were examined for histology and molecularly for BMPR1A "second hits" and mutational signatures. RESULTS: Targeted sequencing of blood DNA revealed a three-nucleotide deletion (BMPR1A c.264_266 del) in one family, a three-nucleotide insertion (BMPR1A c.506_507insTCC) in two families, and a missense change (BMPR1A c.766G > A) in a fourth family. The two families with BMPR1A c.506_507insTCC had a shared ancestral origin. Co-segregation of the variants with colorectal cancer and/or polyps, in-silico modeling, and two hit inactivation by loss of heterozygosity or somatic point mutations in tumors, together with the absence of other possible predisposing variants by exome sequencing, supported the idea of tumor predisposition being attributable to the BMPR1A variants. Polyps examined from variant carriers had adenomatous histology, except for three polyps with hamartomatous features, originating from two BMPR1A carriers from two families. While no hamartoma samples were available for molecular investigation, somatic mutational profiles of colorectal adenomas and carcinomas resembled those of mismatch repair-proficient colorectal tumors in general. CONCLUSIONS: Our findings support the notion that the clinical phenotype of BMPR1A variants may extend beyond classical JPS. Genotype-phenotype correlations are complex, since molecular comparison of constitutional and tumor features of our families to those published from JPS families in the literature show a significant overlap. The variety of clinical phenotypes warrants recognition in the clinical management of BMPR1A carriers and their family members.