ABSTRACT
BACKGROUND: Juvenile Polyposis Syndrome (JPS) is an autosomal dominant condition with hamartomatous polyps in the gastrointestinal tract, associated with an increased risk of gastrointestinal malignancy. Disease causing variants (DCVs) in BMPR1a or SMAD4 account for 45-60% of JPS cases, with BMPR1a DCVs accounting for 17-38% of JPS cases. Within those with either a BMPR1a or SMAD4 DCV, there is phenotypic variability in location of polyps, risk of malignancy and extra-intestinal manifestations with limited published reports of gene-phenotype association or genotype-phenotype correlation. We aimed to identify any gene-phenotype association or genotype-phenotype correlation in BMPR1a to inform surveillance recommendations, and gene-specific modification to the ACMG classification of pathogenicity of DCVs. METHODS: A literature search was performed through EMBASE, MEDLINE and PubMed. Studies that were included explored BMPR1a DCV-related JPS or contiguous deletion of PTEN and BMPR1a. Data was also drawn from the BMPR1a specific databases on LOVD and ClinVar. RESULTS: There were 211 DCVs in BMPR1a identified, 82 from patients with JPS in the literature, and 17 from LOVD and 112 from ClinVar classified as pathogenic or likely pathogenic. These included missense, nonsense and frameshift variants and large deletions, occurring across all functional domains of the gene. Unlike in SMAD4 carriers, gastric polyposis and malignancy were not identified in our review in BMPR1a carriers, but colonic polyposis and malignancy occurred in carriers of either BMPR1a or SMAD4 DCVs. Those with contiguous deletion of PTEN and BMPR1a can present with JPS of infancy, with a severe phenotype of GI bleeding, diarrhoea, exudative enteropathy and rectal prolapse. No specific BMPR1a genotype-phenotype correlation could be ascertained including by variant type or functional domain. CONCLUSION: Phenotypic characteristics cannot be used to inform variant location in BMPR1a. However, the phenotypic characteristics of BMPR1a DCV carriers, being almost exclusively related to the colon and rectum, can assist in pathogenicity assessment of BMPR1a variants. Given these findings, we propose that carriers of BMPR1a DCVs should only require surveillance for colorectal polyps and malignancy, and that surveillance for gastric polyps and malignancy may be unnecessary. However variant location within BMPR1a does not support differential surveillance recommendations.
ABSTRACT
This article provides a historical overview of the online database ( www.insight-group.org/mutations ) maintained by the International Society for Gastrointestinal Hereditary Tumours. The focus is on the mismatch repair genes which are mutated in Lynch Syndrome. APC, MUTYH and other genes are also an important part of the database, but are not covered here. Over time, as the understanding of the genetics of Lynch Syndrome increased, databases were created to centralise and share the variants which were being detected in ever greater numbers. These databases were eventually merged into the InSiGHT database, a comprehensive repository of gene variant and disease phenotype information, serving as a starting point for important endeavours including variant interpretation, research, diagnostics and enhanced global collection. Pivotal to its success has been the collaborative spirit in which it has been developed, its association with the Human Variome Project, the appointment of a full time curator and its governance stemming from the well established organizational structure of InSiGHT.
