scholarly journals A distinct APC pathogenic germline variant identified in a southern Thai family with familial adenomatous polyposis

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Worrawit Wanitsuwan ◽  
Sukanya Vijasika ◽  
Pichai Jirarattanasopa ◽  
Sukanya Horpaopan
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Donor Site ◽  
Family Members ◽  
Colonic Polyps ◽  
Predictive Testing ◽  
Pathogenic Variant ◽  
Splice Donor Site ◽  
Adenomatous Polyposis ◽  
Transcription Analysis ◽  
Pathogenic Variants

Abstract Background Familial adenomatous polyposis (FAP) is caused by pathogenic germline variants in the APC gene. To date, multiple pathogenic variants in coding regions, splice sites, and deep intronic regions have been revealed. However, there are still pathogenic variants that remain unidentified. Methods Twenty-nine primer pairs flanking exons 2–16 (i.e., coding exons 1–15) of APC and their exon–intron junctions were used for germline pathogenic variant screening in Southern Thai patients with familial adenomatous polyposis (FAP). Transcription analysis was performed to confirm the pathogenicity of a splice site deletion of intron 10. Family members were interviewed for clinical histories. Blood samples were collected from 18 family members for a segregation study. Subsequently, clinical data of affected members were collected from the hospital databases. Results We found a distinct heterozygous 16-bp deletion at the splice donor site of intron 10 leading to a skipping of exon 10 which was confirmed by transcript analysis (APC: c 1312 + 4_1312 + 19del, r.934_1312del). Predictive testing for the pathogenic APC variant in 18 of the proband’s family members (ten healthy and eight affected) from three generations showed the same heterozygous germline pathogenic variant in eight affected adult members (15–62 years old) and two children (7 and 10 years old). Seven of the ten carriers of the disease-causing variant had undergone colonoscopy, and colonic polyps were found in all cases, which confirmed the segregation of the inherited pathogenic variant. The phenotypic spectrum was found to vary within the family; and some affected family members exhibited extracolonic manifestations. Conclusions To our knowledge, the pathogenic APC variant, c.1312 + 4_1312 + 19del, r.934_1312del, has not previously been reported. This study is one of the few reports describing the phenotypic consequences of a pathogenic APC variant in a high number of affected family members.

scholarly journals Solid-pseudopapillary neoplasm of the pancreas in a patient with familial adenomatous polyposis: a case report

2021 ◽  
Vol 7 (1) ◽  
Author(s):  
Daishi Naoi ◽  
Koji Koinuma ◽  
Hideki Sasanuma ◽  
Yasunaru Sakuma ◽  
Hisanaga Horie ◽  
...  
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Pancreatic Tumor ◽  
Laparoscopic Resection ◽  
Tumor Development ◽  
Colonic Polyps ◽  
Pancreatic Tumors ◽  
Beta Catenin ◽  
Adenomatous Polyposis ◽  
Solid Pseudopapillary Neoplasm ◽  
Extracolonic Manifestations

Abstract Background Familial adenomatous polyposis (FAP) is characterized by the presence of hundreds to thousands of colonic polyps, and extracolonic manifestations are likely to occur. Pancreatic tumors are rare extracolonic manifestations in patients with FAP, among which solid-pseudopapillary neoplasm (SPN) are extremely rare. We report here a patient with an SPN of the pancreas found during the follow-up of FAP. Case presentation A 20-year-old woman was diagnosed with FAP 3 years previously by colonoscopy which revealed less than 100 colonic polyps within the entire colon. She complained of left upper abdominal pain and a 10-cm solid and cystic pancreatic tumor was found by computed tomography scan. Solid and cystic components within the tumor were seen on abdominal magnetic resonance imaging. Simultaneous laparoscopic resection of the distal pancreas and subtotal colectomy was performed. Histopathological findings confirmed the pancreatic tumor as an SPN without malignancy. Abnormal staining of beta-catenin was observed by immunohistochemical study. Multiple polyps in the colorectum were not malignant. Molecular biological analysis from peripheral blood samples revealed a decrease in the copy number of the promoter 1A and 1B region of the APC gene, which resulted in decreased expression of the APC gene. Conclusions A rare association of SPN with FAP is reported. The genetic background with relation to beta-catenin abnormalities is interesting to consider tumor development. So far, there are few reports of SPN in a patient with FAP. Both lesions were treated simultaneously by laparoscopic resection.

MO039IDENTIFICATION OF A RECURRENT SYNONYMOUS GENETIC VARIANT IN NPHP3 LEADING TO NEPHRONOPHTHISIS AND CONGENITAL HEPATIC FIBROSIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Eric Olinger ◽  
Intisar Al Alawi ◽  
Elisa Molinari ◽  
Eissa Ali Faqeih ◽  
Mohamed Al Hamed ◽  
...  
Keyword(s):  
Candidate Genes ◽  
Rna Splicing ◽  
Donor Site ◽  
Saudi Arabian ◽  
Bioinformatic Analysis ◽  
Initial Assessment ◽  
Splice Donor Site ◽  
Uk Biobank ◽  
Pathogenic Variants ◽  
Exon 20

Abstract Background and Aims Whole exome sequencing (WES) is becoming part of routine clinical and diagnostic practice and has been extensively applied in research studies as well as for diagnostic utility to detect various novel genes and variants. Filtering of variants and scoring variants in terms of pathogenicity still represents a major challenge and may explain why ∼50% of patients remain without diagnosis after initial assessment. Method In this study, we performed WES to determine the genetic cause of a hepato-renal ciliopathy syndrome in a genetically unsolved consanguineous family from Oman with 2 affected children. For variants filtering and annotation Qiagen Clinical Insight tool was used. Database searches for identical alleles in patients with similar phenotypes were performed using Genomics England, UK Biobank and a Saudi Arabian cohort. RNA studies were used to confirm a splicing defect. This research was made possible through access to the data and findings generated by the 100,000 Genomes Project and from UK Biobank, a major biomedical database. Results Initial bioinformatic analysis of WES data from 2 affected sibs excluded obvious pathogenic variants in known genes associated with primary ciliopathy syndromes with liver and kidney phenotypes. However, by manual curation of variants in candidate genes, a rare homozygous synonymous allele in NPHP3 was identified (c.2805C>T; p.(Gly935Gly)), mid-exon 20 and within a region of shared homozygosity on chromosome 3. Correct segregation was confirmed via Sanger sequencing in the parents and the 2 affected sibs. The variant was rare in gnomAD (2/251374 alleles) and was found heterozygously in just one individual within the UK Biobank cohort of 200,000 exomes. Using various in silico tools, the allele was shown to activate a cryptic splice donor site in the middle of exon 20. RT-PCR with sequencing of parental whole blood RNA confirmed alternative splicing leading to frameshift p.Gly935GlyfsTer47. The identical homozygous allele was identified in 2 additional unsolved families within the Genomics England 100,000 Genomes Project and in 1 Saudi Arabian family with similar hepato-renal phenotypes. Conclusion This study shows that automated filtering of WES data may exclude synonymous variants which are pathogenic, especially if they are mid-exon. Here we identified a recurrent synonymous NPHP3 variant leading to a splice defect as the cause of a hepato-renal ciliopathy phenotype in four families. In unsolved cases, rare synonymous alleles in candidate genes need to be reassessed for impact on RNA splicing and possible pathogenicity.

Pancreaticoduodenectomy for Dysplastic Duodenal Adenoma in a Patient with Familial Adenomatous Polyposis

2008 ◽  
Vol 94 (6) ◽  
pp. 882-884
Author(s):  
Roberto Merenda ◽  
Giuseppe Portale ◽  
Francesca Galeazzi ◽  
Chiara Tosolini ◽  
Giacomo Carlo Sturniolo ◽  
...  
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Colonic Polyps ◽  
Clinical History ◽  
Adenomatous Polyposis ◽  
Duodenal Adenoma ◽  
Colorectal Polyposis ◽  
Duodenal Polyps ◽  
Younger Age ◽  
History Of ◽  
Malignant Lesions

Colorectal polyposis is the main feature of familial adenomatous polyposis (FAP), but benign and malignant lesions have also been described in the stomach, duodenum, small bowel, biliary tract and pancreas. There are few reports on FAP patients with duodenal polyps that developed at a younger age and even fewer on cases with dysplastic degeneration. The progression to carcinoma usually presents quite late in the clinical history of FAP patients, typically at least 20 to 25 years after proctocolectomy. This report described the rare case of a patient presenting with duodenal adenomas with dysplastic changes and tumor infiltration as the first sign of FAP, who was treated by pancreaticoduodenectomy followed by proctocolectomy for subsequent dysplastic changes in colonic polyps.

Patterns of Adenoma Recurrence in Familial Adenomatous Polyposis Patients after Ileal Pouch-Anal Anastomosis

2015 ◽  
Vol 32 (6) ◽  
pp. 421-425 ◽  
Author(s):  
Adam L. Goldstein ◽  
Revital Kariv ◽  
Joseph M. Klausner ◽  
Hagit Tulchinsky
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Desmoid Tumor ◽  
Ileal Pouch ◽  
Medical Center ◽  
Colonic Polyps ◽  
Ileal Pouch Anal Anastomosis ◽  
Adenomatous Polyposis ◽  
Adenoma Recurrence ◽  
Duodenal Adenomas ◽  
Anal Anastomosis

Aim: This study aims at identifying the risk factors for the development of pre-cancerous pouch and/or cuff adenomas post ileal pouch anal anastomosis (IPAA) in familial adenomatous polyposis patients. Method: We retrospectively studied 59 patients operated at a single medical center during a 26-year period. Data on the timing and location of adenoma recurrence were recorded and possible correlations with patients' gender, age, presence of desmoid tumor, duodenal adenomas, type of anastomosis and number of operation stages were analyzed. Results: Thirty-five (59%) patients had at least one adenoma in either the cuff or the pouch, including 20 with isolated cuff adenomas, 4 with isolated pouch adenomas and 11 patients with adenomas in both the pouch and cuff. There was no significant correlation between gender, age at surgery, type of anastomosis, number of operative stages and the development of pouch or cuff adenomas. Desmoid tumor and pouch adenomas were significantly correlated with cuff adenomas formation. Duodenal adenomas were associated with pouch adenomas. There was some relationship between the development of cuff adenomas and the burden of colonic polyps, as well as the presence of duodenal adenomas. Conclusion: Adenomas in both the pouch and cuff commonly occur following IPAA, mandating lifelong annual endoscopic surveillance.

Variable Phenotypic Expression of Identical MYH Germline Mutations in Siblings with Attenuated Familial Adenomatous Polyposis

2007 ◽  
Vol 73 (12) ◽  
pp. 1250-1253 ◽  
Author(s):  
Mustafa Raoof ◽  
Robert J. Canter ◽  
Philip B. Paty
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Locally Advanced ◽  
Phenotypic Expression ◽  
Clinical Manifestations ◽  
Colon Adenocarcinoma ◽  
Colonic Polyps ◽  
Germline Mutations ◽  
Adenomatous Polyposis ◽  
Attenuated Familial Adenomatous Polyposis ◽  
Myh Gene

Germline mutations in the Mutant-Y-homologue (MYH) gene have been linked to an attenuated form of familial adenomatous polyposis in patients who express a wild-type adenomatous polyposis coli gene. However, the diverse clinical manifestations of MYH mutations have not been fully elucidated. We report a case of siblings with identical germline mutations in the MYH gene, one of whom developed a locally advanced colon adenocarcinoma with few other adenomatous lesions, whereas the other had numerous benign colonic polyps. The variable genotype–phenotype manifestations of MYH mutations and the attenuated familial adenomatous polyposis syndrome are discussed.

scholarly journals A splice donor variant in CCDC189 is associated with asthenospermia in Nordic Red dairy cattle

2018 ◽  
Author(s):  
Terhi Iso-Touru ◽  
Christine Wurmser ◽  
Heli Venhoranta ◽  
Maya Hiltpold ◽  
Tujia Savolainen ◽  
...  
Keyword(s):  
Donor Site ◽  
Coiled Coil ◽  
Reproductive Traits ◽  
Mendelian Inheritance ◽  
Splice Donor Site ◽  
Splice Donor ◽  
Transcription Analysis ◽  
Gene Test ◽  
Collection Period ◽  
Physiological Movement

AbstractBackgroundCattle populations are highly amenable to the genetic mapping of male reproductive traits because longitudinal data on ejaculate quality and dense microarray-derived genotypes are available for many artificial insemination bulls. Two young Nordic Red bulls delivered sperm with low progressive motility (i.e., asthenospermia) during a semen collection period of more than four months. The bulls were related through a common ancestor on both their paternal and maternal ancestry. Thus, a recessive mode of inheritance of asthenospermia was suspected.ResultsBoth bulls were genotyped at 54,001 SNPs using the Illumina BovineSNP50 Bead chip. A scan for autozygosity revealed that they were identical by descent for a 2.98 Mb segment located on bovine chromosome 25. This haplotype was not found in the homozygous state in 8,557 fertile bulls although five homozygous haplotype carriers were expected (P=0.018). Whole genome-sequencing uncovered that both asthenospermic bulls were homozygous for a mutation that disrupts a canonical 5’ splice donor site of CCDC189 encoding the coiled-coil domain containing protein 189. Transcription analysis showed that the derived allele activates a cryptic splice site resulting in a frameshift and premature termination of translation. The mutated CCDC189 protein is truncated by more than 40%, thus lacking the flagellar C1a complex subunit C1a-32 that is supposed to modulate the physiological movement of the sperm flagella. The mutant allele occurs at a frequency of 2.5% in Nordic Red cattle.ConclusionsOur study in cattle uncovered that CCDC189 is required for physiological movement of sperm flagella thus enabling active progression of spermatozoa and fertilization. A direct gene test may be implemented to monitor the asthenospermia-associated allele and prevent the birth of homozygous bulls that are infertile. Our results have been integrated in the Online Mendelian Inheritance in Animals (OMIA) database (https://omia.org/OMIA002167/9913/).

scholarly journals Clinical Implications of Identifying Pathogenic Variants in Individuals With Thoracic Aortic Dissection

2019 ◽  
Vol 12 (6) ◽  
Author(s):  
Brooke N. Wolford ◽  
Whitney E. Hornsby ◽  
Dongchuan Guo ◽  
Wei Zhou ◽  
Maoxuan Lin ◽  
...  
Keyword(s):  
Family History ◽  
Aortic Dissection ◽  
Age Of Onset ◽  
Family Members ◽  
Aortic Disease ◽  
Pathogenic Variant ◽  
Carrier Status ◽  
Thoracic Aortic Dissection ◽  
Pathogenic Variants ◽  
History Of

Background: Thoracic aortic dissection is an emergent life-threatening condition. Routine screening for genetic variants causing thoracic aortic dissection is not currently performed for patients or family members. Methods: We performed whole exome sequencing of 240 patients with thoracic aortic dissection (n=235) or rupture (n=5) and 258 controls matched for age, sex, and ancestry. Blinded to case-control status, we annotated variants in 11 genes for pathogenicity. Results: Twenty-four pathogenic variants in 6 genes (COL3A1, FBN1, LOX, PRKG1, SMAD3, and TGFBR2) were identified in 26 individuals, representing 10.8% of aortic cases and 0% of controls. Among dissection cases, we compared those with pathogenic variants to those without and found that pathogenic variant carriers had significantly earlier onset of dissection (41 versus 57 years), higher rates of root aneurysm (54% versus 30%), less hypertension (15% versus 57%), lower rates of smoking (19% versus 45%), and greater incidence of aortic disease in family members. Multivariable logistic regression showed that pathogenic variant carrier status was significantly associated with age <50 (odds ratio [OR], 5.5; 95% CI, 1.6–19.7), no history of hypertension (OR, 5.6; 95% CI, 1.4–22.3), and family history of aortic disease (mother: OR, 5.7; 95% CI, 1.4–22.3, siblings: OR, 5.1; 95% CI, 1.1–23.9, children: OR, 6.0; 95% CI, 1.4–26.7). Conclusions: Clinical genetic testing of known hereditary thoracic aortic dissection genes should be considered in patients with a thoracic aortic dissection, followed by cascade screening of family members, especially in patients with age-of-onset <50 years, family history of thoracic aortic disease, and no history of hypertension.

scholarly journals Prevalence of Gastroduodenal Polyps in Children With Familial Adenomatous Polyposis

2020 ◽  
Author(s):  
James K Stone ◽  
Charles N Bernstein ◽  
Harminder Singh ◽  
Wael El-Matary
Keyword(s):  
Familial Adenomatous Polyposis ◽  
Large Scale ◽  
Colonic Polyps ◽  
Colorectal Polyp ◽  
Adenomatous Polyps ◽  
Adenomatous Polyposis ◽  
Early Screening ◽  
Endoscopic Screening ◽  
Screening Endoscopy ◽  
Upper Gastrointestinal

Abstract Objective To assess the prevalence of upper gastrointestinal adenomatous polyps in a cohort of pediatric familial adenomatous polyposis (FAP) patients to determine if early screening is warranted. Study Design All 11 pediatric FAP patients diagnosed in Manitoba between January 2012 and December 2019 were recruited. Patient records were examined and data on age of diagnosis, gene mutation, age of first screening endoscopy, number of endoscopies, number of gastric and colonic polyps, associated pathology, medications, symptoms and FAP-related surgeries were extracted and descriptive statistics reported. Results A total of 11 children were diagnosed with FAP over the study period with a mean age at diagnosis of 6.3 ± 3.2 years with 72.3% males and median follow-up of 4.8 years. The mean age at first gastroscopy was 10.9 ± 2.9 years and 10.8 ± 3.0 years at colonoscopy. Eight patients (72%) had upper gastrointestinal polyps, with adenomatous changes seen in seven of them on pathology. No patients had invasive carcinoma or high-grade dysplasia. All patients developed tubular adenomas on colorectal polyp pathology. Four (36%) patients underwent surgical colectomy. Conclusions Early-onset upper gastrointestinal adenomatous polyps in a pediatric FAP are common. Our study provides further data to support consideration of further, large-scale research into the benefit of early endoscopic screening for upper gastrointestinal malignancy in FAP patients.

scholarly journals Cost comparison of predictive genetic testing versus conventional clinical screening for familial adenomatous polyposis

Gut ◽  
1999 ◽  
Vol 44 (5) ◽  
pp. 698-703 ◽  
Author(s):  
B Bapat ◽  
H Noorani ◽  
Z Cohen ◽  
T Berk ◽  
A Mitri ◽  
...  
Keyword(s):  
At Risk ◽  
Genetic Testing ◽  
Familial Adenomatous Polyposis ◽  
Family Members ◽  
Screening Strategy ◽  
Predictive Genetic Testing ◽  
Cost Comparison ◽  
Adenomatous Polyposis ◽  
Clinical Screening ◽  
The Cost

BACKGROUNDMutations of theAPC gene cause familial adenomatous polyposis (FAP), a hereditary colorectal cancer predisposition syndrome.AIMSTo conduct a cost comparison analysis of predictive genetic testing versus conventional clinical screening for individuals at risk of inheriting FAP, using the perspective of a third party payer.METHODSAll direct health care costs for both screening strategies were measured according to time and motion, and the expected costs evaluated using a decision analysis model.RESULTSThe baseline analysis predicted that screening a prototype FAP family would cost $4975/£3109 by molecular testing and $8031/£5019 by clinical screening strategy, when family members were monitored with the same frequency of clinical surveillance (every two to three years). Sensitivity analyses revealed that the genetic testing approach is cost saving for key variables including the kindred size, the age of screening onset, and the cost of mutation identification in a proband. However, if theAPC mutation carriers were monitored at an increased (annual) frequency, the cost of the genetic screening strategy increased to $7483/£4677 and was especially sensitive to variability in age of onset of screening, family size, and cost of genetic testing of at risk relatives.CONCLUSIONSIn FAP kindreds, a predictive genetic testing strategy costs less than conventional clinical screening, provided that the frequency of surveillance is identical using either strategy. An additional significant benefit is the elimination of unnecessary colonic examinations for those family members found to be non-carriers.

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