BMPR1A and SMAD4 mutations in juvenile polyposis syndrome: clinicopathological and genetic data from two congolese patients

Poaty, Henriette; Bouya, Lauria Batamba; Ondima, Irène Patricia Lucienne; Mongo-Onkouo, Arnaud; Zola, Aimé Lumaka; Peko, J. F.; Gassaye, Déby

doi:10.1016/j.genrep.2021.101141

Cited by 3 publications

(3 citation statements)

References 22 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Two had a duplication in the MH1 Domain: one with a c.351dup (p.Leu118AlafsTer14) was diagnosed at age eight with innumerable colorectal polyps [ 22 ], and the other with a c.405dup (p.Pro136ThrfsTer13) who was diagnosed at age seven with 30 colorectal polyps [ 22 ]. One had a deletion in the MH1 Domain, c.435delG (p.Phe147LeufsTer18), was diagnosed at age nine with > 50 colorectal polyps [ 24 ] and one had a deletion in the Intracellular Domain, c.888delT (p.Gly298ValfsTer10), was diagnosed at age five with > 50 colorectal polyps [ 17 , 21 ].…”

Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome

Papadopulos

Plazzer

Macrae

2023

Hered Cancer Clin Pract

View full text Add to dashboard Cite

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.

show abstract

Section: Resultsmentioning

confidence: 99%

Genotype–phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome

Papadopulos

Plazzer

Macrae

2023

Hered Cancer Clin Pract

View full text Add to dashboard Cite

show abstract

Section: Patient and Methodsmentioning

confidence: 99%

“…The proband is a 51 year-old-Congolese male, recruited at the Gastroenterology and Cancerology Services of the Brazzaville Teaching Hospital, Congo in the frame of a research study hereditary on CRC in Brazzaville. 6,10 He had personal medical problems evolving for 8 years. It all started with diarrhea and abdominal pains, followed by rectal bleeding, significant weight loss, and anemia.…”

Section: Patientmentioning

confidence: 99%

PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps

et al. 2023

Self Cite

View full text Add to dashboard Cite

Background Lynch syndrome (LS) is an autosomal dominant condition due to the germline mutation in the mismatch repair (MMR) genes including MLH1, MSH2, MSH6, and PMS2 (post-meiotic segregation increased 2). The MMR mutation carriers have high risk for cancers. Pathogenic PMS2 variants are rarely reported in LS-associated colorectal cancer (CRC) with colorectal polyps. The aim of the study was to investigate the genetic etiology of CRC in an individual with CRC with multiple colorectal polyps and a family history of cancers. Patients and Methods The index patient was an African male affected by CRC with multiple colorectal polyps. The clinical diagnostic for LS was based on the Amsterdam II criteria and pedigree. Next-generation sequencing with inherited cancer genes panel was used to detect the pathogenic variant. Results The patient fulfilled the Amsterdam II criteria and the pedigree revealed a family history of recurrent CRC. A deleterious PMS2 germline heterozygous mutation c.2192_2196delTAACT was detected. Conclusion Our study supports the notion that LS may be associated with polyps and shows the predisposition of PMS2 heterozygous mutation in LS-associated CRC at young age.

show abstract

SMAD4 variants and its genotype–phenotype correlations to juvenile polyposis syndrome

Cao,

Plazzer,

Macrae

2023

Hered Cancer Clin Pract

View full text Add to dashboard Cite

Background Juvenile polyposis syndrome (JPS), a rare autosomal dominant syndrome, affects one per 100 000 births, increasing lifetime cancer risk by 9 – 50%. Around 40–60% of JPS cases are caused by disease-causing variants (DCV) in SMAD4 or BMPR1A genes, of which SMAD4 accounts for 20–30%. Objectives To characterise genotype–phenotype correlations between sites and types of variants within SMAD4 to JPS phenotypes, to inform diagnosis, screening, and management of JPS. Search methods Online search databases utilised included Ovid MEDLINE, Embase Classic + Embase and PubMed, using search terms classified by MeSH on Demand. Adjacency operators, word truncation and Boolean operators were employed. 110 articles were included in the review, collating 291 variants from the literature. Results In SMAD4 + JPS patients, most variants are located around SMAD4’s MH2 domain (3’ end). Extracolonic involvement, massive gastric polyposis and a more aggressive phenotype have been associated with SMAD4 + JPS, predisposing to gastric cancer. This has contributed to an overall higher incidence of GI cancers compared to other genes causing JPS, with DCVs mostly all within the MH2 domain. Genetically related allelic disorders of SMAD4 also have variants in this region, including hereditary haemorrhagic telangiectasia (HHT) alongside SMAD4 + JPS, and Myhre syndrome, independent of JPS. Similarly, with DCVs in the MH2 domain, Ménétrier’s disease, hypertrophic osteoarthropathy and juvenile idiopathic arthritis have been seen in this population, whereas cardiac pathologies have occurred both alongside and independently of SMAD4 + JPS with DCVs in the MH1 domain. Conclusion Truncating and missense variants around the MH2 region of SMAD4 are most prevalent and pathogenic, thus should undergo careful surveillance. Given association with extracolonic polyposis and higher GI cancer risk, endoscopic screening should occur more frequently and at an earlier age in SMAD4 + JPS patients than in patients with other causative genes, with consideration of Ménétrier’s disease on upper GI endoscopy. In addition, HHT should be evaluated within 6 months of diagnosis, alongside targeted clinical examination for extraintestinal manifestations associated with SMAD4 + JPS. This review may help modify clinical diagnosis and management of SMAD4 + JPS patients, and aid pathogenicity classification for SMAD4 DCVs through a better understanding of the phenotypes.

show abstract

BMPR1A and SMAD4 mutations in juvenile polyposis syndrome: clinicopathological and genetic data from two congolese patients

Cited by 3 publications

References 22 publications

Genotype–phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome

Genotype–phenotype correlation of BMPR1a disease causing variants in juvenile polyposis syndrome

PMS2 Pathogenic Variant in Lynch Syndrome-Associated Colorectal Cancer with Polyps

SMAD4 variants and its genotype–phenotype correlations to juvenile polyposis syndrome

Contact Info

Product

Resources

About