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Objective:
A subgroup of patients with hamartomatous polyps in the GI tract has a hereditary Hamartomatous Polyposis Syndrome with an increased risk of cancer. The distinction between patients with one or few polyps and patients with a syndrome can be difficult. A pathogenic germline mutation can be detected in a majority of HPS patients. This stu...
Context in source publication
Context 1
... reads were aligned to the human reference gen- ome (build hg19) by NovoAlign v. Figure 2. Variants with minor allele frequency reported at greater than 1% in the 1000 Genomes Project and ESP, and intronic variants outside consensus splice site boundaries were considered not pathogenic and were excluded from fur- ther analysis. ...
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Germline mutations of the APC gene are associated with an autosomal dominant precancerous condition, termed familial adenomatous polyposis (FAP). FAP is clinically manifested by the presence of multiple colorectal adenomas or polyps. Gradually, these colorectal adenomas or polyps inevitably result in colorectal cancer by the third-to fourth decade...
Importance
Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention.
Objective
To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tiss...
Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition which is associated with germline mutations of the APC gene. Clinically, FAP is characterized by the development of multiple colorectal adenomas or polyps which finally result in colorectal cancer by the 40 years age of the patient, if no surgical interventions hav...
Half of the high-risk colorectal cancer families that fulfill the clinical criteria for Lynch syndrome lack germline mutations in the mismatch repair (MMR) genes and remain unexplained. Genetic testing for hereditary cancers is rapidly evolving due to the introduction of multigene panels, which may identify more mutations than the old screening met...
Background:
Genetic screening to identify carriers of autosomal recessive diseases has become an integral part of routine prenatal care. In spite of the rapid growth of known mutations, most current screening programs include only a small subset of these mutations, and are performed using diverse molecular techniques, which are generally labor-int...
Citations
... Location and type of DCVs in BMPR1a identified in the literature and pathogenic or likely pathogenic variants from LOVD and ClinVar[3,9,10,14,[16][17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34] ...
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.
... This also indicates that SMAD4 and BMPR1A should be included in the panel of genes analyzed in all patients suspected to suffer from a genetic predisposition to intestinal polyposis. However, the varying histopathology can also be due to misclassification of polyps in the first place as have been reported before [7,21]. In general, it can be difficult to distinguish different types of polyps from each other and especially juvenile polyps can resemble inflammatory polyps. ...
Juvenile polyposis syndrome (JPS) is a hereditary hamartomatous polyposis syndrome characterized by gastrointestinal juvenile polyps and increased risk of gastrointestinal cancer. Germline pathogenic variants are detected in SMAD4 or BMPR1A, however in a significant number of patients with JPS, the etiology is unknown. From Danish registers, and genetic department and laboratories, we identified all patients in Denmark with a clinical diagnosis of JPS and/or a pathogenic variant in BMPR1A or SMAD4. In patients where no variant had been detected, we performed genetic analysis, including whole genome sequencing. We collected clinical information on all patients to investigate the phenotypic spectrum. Sixty-six patients (mean age 40 years) were included of whom the pathogenic variant was unknown in seven patients. We detected a pathogenic variant in SMAD4 or PTEN in additional three patients and thus ≈ 95% of patients had a pathogenic germline variant. Endoscopic information was available in fifty-two patients (79%) and of these 31 (60%) fulfilled the clinical criteria of JPS. In 41 patients (79%), other types of polyps than juvenile had been removed. Our results suggest that almost all patients with a clinical diagnosis of JPS has a pathogenic variant in mainly BMPR1A, SMAD4, and more rarely PTEN. However, not all patients with a pathogenic variant fulfil the clinical criteria of JPS. We also demonstrated a wide clinical spectrum, and that the histopathology of removed polyps varied.
... The next example is the c.424+5G>A variant at the 8th exon splice donor site of SMAD4. Although this variant has an even smaller allele frequency (19/151,834, (0.0125%)), it has been reported in several cancer-cohort studies [43][44][45] . Previous studies have described this variant as a variant of uncertainty significance even though they pointed out the possibility that it causes some kind of abnormal splicing. ...
Many disease-associated genomic variants disrupt gene function through abnormal splicing. With the advancement of genomic medicine, identifying disease-associated splicing associated variants has become more important than ever. Most bioinformatics approaches to detect splicing associated variants require both genome and transcriptomic data. However, there are not many datasets where both of them are available. In this study, we develop a methodology to detect genomic variants that cause splicing changes (more specifically, intron retention), using transcriptome sequencing data alone. After evaluating its sensitivity and precision, we apply it to 230,988 transcriptome sequencing data from the publicly available repository and identified 27,049 intron retention associated variants (IRAVs). In addition, by exploring positional relationships with variants registered in existing disease databases, we extract 3,000 putative disease-associated IRAVs, which range from cancer drivers to variants linked with autosomal recessive disorders. The in-silico screening framework demonstrates the possibility of near-automatically acquiring medical knowledge, making the most of massively accumulated publicly available sequencing data. Collections of IRAVs identified in this study are available through IRAVDB (https://iravdb.io/).
... JPS is inherited in an autosomal dominant manner. The distinction between patientsespecially childrenwith solitary or few juvenile polyps from juvenile polyposis can be difficult, but for patients with only one juvenile polyp the risk for having JPS is low [13]. The risk of CRC and gastric cancer is increased with the risk of gastric polyposis, gastric cancer being highest in SMAD4 carriers [14]. ...
Hereditary Polyposis Syndromes are a group of rare, inherited syndromes characterized by the presence of histopathologically specific or numerous intestinal polyps and an increased risk of cancer. Some polyposis syndromes have been known for decades, but the development in genetic technologies has allowed the identification of new syndromes.. The diagnosis entails surveillance from an early age, but universal guideline on how to manage and surveille these new syndromes are lacking. This paper represents a condensed version of the recent guideline (2020) from a working group appointed by the Danish Society of Medical Genetics and the Danish Society of Surgery on recommendations for the surveillance of patients with hereditary polyposis syndromes, including rare polyposis syndromes.
... The next example is the c.424+5G>A variant at the 8th exon splice donor site of SMAD4. Although this variant has an even smaller allele frequency (19/151,834, (0.0125%)), it has been reported in several cancer-cohort studies [37][38][39] . Previous studies have described this variant as a variant of uncertainty significance even though they pointed out the possibility that it causes some kind of abnormal splicing. ...
Many disease-associated genomic variants disrupt gene function through abnormal splicing. With the advancement of genomic medicine, identifying disease-associated splicing associated variants has become more important than ever. Most bioinformatics approaches to detect splicing associated variants require both genome and transcriptomic data. However, there are not many datasets where both of them are available. In this study, we developed a methodology to detect genomic variants that cause splicing changes (more specifically, intron retention), using transcriptome sequencing data alone. After demonstrating its high sensitivity and precision, we have applied it to 230,988 transcriptome sequencing data from the publicly available repository and identified 27,937 intron retention associated variants (IRAVs). In addition, by exploring positional relationships with variants registered in existing disease databases, we extracted 3,077 putative disease-associated IRAVs, which range from cancer drivers to variants linked with autosomal recessive disorders. The new in-silico screening framework proposed here provides a foundation for a platform that can automatically acquire medical knowledge making the most of massively accumulated publicly available sequencing data. Collections of IRAVs identified in this study are available through IRAVDB (https://iravdb.io/).
... A further study is needed, i.e. functional study to prove that this new de novo missense variant in exon 3 BMPR1A gene in this study is pathogenic variant. Missense variants of BMPR1A gene identified in JPS patients reported in PubMed from 2000 to 2019, including the present case, are summarized in Table 1, with the pathogenicity evaluated according to ACMG guidelines [6,10,[13][14][15][16][17][18][19][20][21][22][23][24][25]. Most of the previous reported missense variants are classified as VUS except for c.1328G > A, another de novo missense variant listed as likely pathogenic [24]. ...
Background:
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant hereditary disorder characterized by the development of multiple distinct juvenile polyps in the gastrointestinal tract with an increased risk of colorectal cancer. Germline mutations in two genes, SMAD4 and BMPR1A, have been identified to cause JPS.
Case presentation:
Here, we report a germline heterozygous missense variant (c.299G > A) in exon 3 BMPR1A gene in a family with juvenile polyposis. This variant was absent from the population database, and concluded as de novo compared with the parental sequencing. Further sequencing of the proband's children confirmed the segregation of this variant with the disease, while the variant was also predicted to have damaging effect based on online prediction tools. Therefore, this variant was classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) guidelines.
Conclusions:
Germline genetic testing revealed a de novo germline missense variant in BMPR1A gene in a family with juvenile polyposis. Identification of the pathogenic variant facilitates the cancer risk management of at-risk family members, and endoscopic surveillance is recommended for mutation carriers.
... A similar smaller study of 77 individuals who had ''few'' hamartomatous polyps did not yield any positive genetic results. 22 These results may imply that individuals with few polyps will benefit less from evaluation for genetic etiology than CRC-affected individuals. However, stratifying by number of polyps, which is not possible with these data, would be expected to clarify the rate of positive findings. ...
As clinical testing for Mendelian causes of colorectal cancer (CRC) is largely driven by recognition of family history and early age of onset, the rates of such findings among individuals with prevalent CRC not recognized to have these features is largely unknown. We evaluated actionable genomic findings in community-based participants ascertained by three phenotypes: (1) CRC, (2) one or more adenomatous colon polyps, and (3) control participants over age 59 years without CRC or colon polyps. These participants underwent sequencing for a panel of genes that included colorectal cancer/polyp (CRC/P)-associated and actionable incidental findings genes. Those with CRC had a 3.8% rate of positive results (pathogenic or likely pathogenic) for a CRC-associated gene variant, despite generally being older at CRC onset (mean 72 years). Those ascertained for polyps had a 0.8% positive rate and those with no CRC/P had a positive rate of 0.2%. Though incidental finding rates unrelated to colon cancer were similar for all groups, our positive rate for cardiovascular findings exceeds disease prevalence, suggesting that variant interpretation challenges or low penetrance in these genes. The rate of HFE c.845G>A (p.Cys282Tyr) homozygotes in the CRC group reinforces a previously reported, but relatively unexplored, association between hemochromatosis and CRC. These results in a general clinical population suggest that current testing strategies could be improved in order to better detect Mendelian CRC-associated conditions. These data also underscore the need for additional functional and familial evidence to clarify the pathogenicity and penetrance of variants deemed pathogenic or likely pathogenic, particularly among the actionable genes associated with cardiovascular disease.
Objectives:
Cronkhite-Canada syndrome (CCS) is a rare hamartomatous polyposis syndrome (HPS) with a proposed association with chronic autoimmune inflammation. To date, the genetic background in patients with CCS remains less investigated. This study set out to explore the genomic landscape of CCS.
Methods:
Whole-exome sequencing (WES) was performed on peripheral blood samples from 18 patients with CCS. Potential function-impacting germline variants were filtered by R. Through systematic data analysis, a number of genetic variants were released. Enrichment analyses were performed using the R package ClusterProfiler.
Results:
Overall, 3960 low-frequency (< 0.05 or not reported in the ExAC East Asian, 1000 Genomes or ESP6500 database) potentially function-impacting germline variants were identified, with 18 genes (FDFT1, LOC400863, MUC3A, MUC4, ZNF806, GXYLT1, MUC6, PABPC3, PSPH, ZFPM1, CIC, LOC283710, ARSD, GOLGA6L2, LOC388282, SLC25A5, TMEM247, WDR89) involved in all patients. Functional enrichment of those genes revealed several biological processes in relation to innate immune responses and glycosylation. Only one likely pathogenic germline variant of an HPS-associated gene, PTCH1, was detected in one patient.
Conclusions:
CCS has genomic alteration patterns completely distinct from those of traditional HPSs. The germline mutation landscape indicates potential roles of innate immune responses and glycosylation in CCS pathogenesis. This article is protected by copyright. All rights reserved.
