Papadopulos M E, Plazzer J P, Macrae F A
Department of Medicine, University of Melbourne, The Royal Melbourne Hospital, Melbourne, Australia.
Department of Colorectal Medicine and Genetics, The Royal Melbourne Hospital, Melbourne, Australia.
Hered Cancer Clin Pract. 2023 Jul 3;21(1):12. doi: 10.1186/s13053-023-00255-3.
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.
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.
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.
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.
青少年息肉病综合征（JPS）是一种常染色体显性疾病，胃肠道存在错构瘤性息肉，患胃肠道恶性肿瘤的风险增加。BMPR1a或SMAD4中的致病变异（DCV）占JPS病例的45 - 60%，其中BMPR1a DCV占JPS病例的17 - 38%。在携带BMPR1a或SMAD4 DCV的患者中，息肉位置、恶性肿瘤风险和肠外表现存在表型变异性，关于基因 - 表型关联或基因型 - 表型相关性的已发表报告有限。我们旨在确定BMPR1a中是否存在任何基因 - 表型关联或基因型 - 表型相关性，以指导监测建议，并对ACMG致病性分类中的DCV进行基因特异性修改。
通过EMBASE、MEDLINE和PubMed进行文献检索。纳入的研究探讨了BMPR1a DCV相关的JPS或PTEN和BMPR1a的连续缺失。数据还来自LOVD和ClinVar上的BMPR1a特定数据库。
共鉴定出211个BMPR1a中的DCV，其中82个来自文献中JPS患者，17个来自LOVD，112个来自ClinVar，分类为致病或可能致病。这些包括错义、无义、移码变异和大片段缺失，发生在该基因的所有功能域。与SMAD4携带者不同，在我们的综述中，BMPR1a携带者未发现胃息肉和恶性肿瘤，但BMPR1a或SMAD4 DCV携带者中出现结肠息肉和恶性肿瘤。PTEN和BMPR1a连续缺失的患者可表现为婴儿期JPS，具有胃肠道出血、腹泻、渗出性肠病和直肠脱垂的严重表型。无法确定BMPR1a的特定基因型 - 表型相关性，包括变异类型或功能域。
表型特征不能用于确定BMPR1a中的变异位置。然而，BMPR1a DCV携带者的表型特征几乎完全与结肠和直肠相关，可有助于评估BMPR1a变异的致病性。基于这些发现，我们建议BMPR1a DCV携带者仅需监测结直肠息肉和恶性肿瘤，而监测胃息肉和恶性肿瘤可能不必要。然而，BMPR1a内的变异位置不支持差异化的监测建议。
