Table 2.
Extended phenotypic spectrum beyond JPS attributed to pathogenic or likely pathogenic variants of BMPR1A.
| Disease phenotype | Disease description | Mean/median age at diagnosis | Detection method | Mutation type∗ | Mutation proportion | Other conditions | Reference |
| HMPS | Polyps are mixed adenomatous, hyperplastic, or atypical juvenile histology, probably eventually leading to CRC. | 33–61 y | Sequence analysis and MLPA | Large genomic deletion, small deletion, or nonsense | 4/8 families (50%) | CRC, thyroid cancer and wilms tumor | [14–16] |
| Other polyposis | Including unexplained hereditary adenomatous polyposis > 100 polyps, unexplained adenomatous polyposis with unknown inheritance, and mixed polyposis | 50 y | NGS and CNV analysis | Frameshift, splicing or missense | 3/23 patients (13%) | A patient with an atypical polyposis carrying both BMPR1A and CHEK2 variants. | [17] |
| FCCTX | It is a type of hereditary nonpolyposis colorectal cancer based on Amsterdam criteria for Lynch syndrome, which has no germline mutation in MMR, and the tumors are microsatellite stable. | 54.6 y | Genetic linkage analysis and mutation analysis | Small deletion | 2/18 families (11%) | CRC, lymphoma, scirrhous carcinoma in breast, etc. | [18] |
| Sporadic early-onset CRC with MMR proficiency | Early-onset (<50 y) CRC without MMR deficiency, no previous polyposis and no CRC family history | NA | Affymetrix 6.0 array | Large genomic deletion (a 7.326-Mb heterozygous deletion in the 10q22-q23 region including BMPR1A) | NA | NA | [19] |
| Superior coloboma | A congenital ocular anomaly characterized by gaps in the tissues of the superior eye | 9.5 y | NGS and functional experiment | Missense | 1/5 patients (20%) | NA | [20] |
| CHD | A most common organ malformations in the newborns, including atrioventricular septal defects, an atrial septal defect, and a ventricular septal defect. | NA | Genome-wide human SNP Array 6.0 and functional experiment | Missense | 12/19 members in one family | A single patient suffered from “severe malformations” before his death during the first days after birth. No extra-cardiac anomalies were reported in this family. | [21] |
CHD = congenital heart diseases, CNV = copy number variation, FCCTX = familial colorectal cancer type X, HMPS = hereditary mixed polyposis syndrome, MLPA = multiplex ligation-dependent probe amplification, MMR = mismatch repair gene, MMR = mismatch repair gene, NA = not available, NGS = next-generation sequencing.
∗
All pathogenic or likely pathogenic variants above were heterozygous.