Paired Somatic-Germline Testing of 15 Polyposis and Colorectal Cancer–Predisposing Genes Highlights the Role of APC Mosaicism in de Novo Familial Adenomatous Polyposis

Rofes, Paula; González, Sara; Navarro, Matilde; Moreno-Cabrera, José Marcos; Solanes, Ares; Darder, Esther; Carrasco, Estela; Iglesias, Sílvia; Salinas, Mónica; Gómez, Carolina; Velasco, Ángela; Tuset, N; Varela, Mar; Llort, Gemma; Cajal, Teresa Ramón y; Grau, Èlia; Dueñas, Nuria; Merlano, Napoleón de la Ossa; Matías‐Guiu, Xavier; Rivera, Bárbara; Balmañà, Judith; Pineda, Marta; Brunet, Joan; Capellà, Gabriel; Valle, Jesús Del; Lázaro, Conxi

doi:10.1016/j.jmoldx.2021.07.024

Cited by 11 publications

(9 citation statements)

References 34 publications

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“…The selected family showed obvious clinical features of classical FAP and the appearance of the disease in several generations indicated the conclusive presence of a heritable factor and ruled out mosaicism [12]. However, routine genetic testing failed to detect a causative germline susceptibility variant in the APC.…”

Section: Discussionmentioning

confidence: 97%

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

et al. 2023

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Familial adenomatous polyposis (FAP) is a hereditary cancer syndrome that occurs as a result of germline mutations in the APC gene. Despite a clear clinical diagnosis of FAP, a certain proportion of the APC variants are not readily detectable through conventional genotyping routines. We accomplished genome sequencing in duo of the disease-affected proband and non-affected sibling followed by in silico predictions and a series of RNA-based assays clarifying variant functionality. By prioritizing variants obtained by genome sequencing, we discovered the novel deep intronic alteration APC:c.531 + 1482 A > G that was demonstrated to cause out-of-frame exonization of 56 base pairs from intron 5 of the gene. Further cDNA assays confirmed, that the aberrant splicing event was complete and its splice product was subject to nonsense-mediated decay. Co-segregation was observed between the variant carrier status and the disease phenotype. Cumulative evidence confirmed that APC:c.531 + 1482 A > G is a pathogenic variant causative of the disease.

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Section: Discussionmentioning

confidence: 97%

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

et al. 2023

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“…Remarkably, splicing variants are the genetic cause of HS in several patients, but intronic regions are not commonly included in genetic testing, even if these variants are found in DNA. Genetic testing should be carried out whenever possible to confirm the diagnosis [ 20 ]. Further RNA analysis is also recommended for assessing the pathogenicity of the variants to reduce the misdiagnosis and underdiagnosis of HS.…”

Section: Discussionmentioning

confidence: 99%

De novo variations of ANK1 gene caused hereditary spherocytosis in two Chinese children by affecting pre-mRNA splicing

et al. 2023

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Background and aims Hereditary spherocytosis (HS) is one of the most common hereditary haemolytic disorders. Here, two unrelated families with the probands displaying typical manifestations of HS were enrolled. Our study aimed to characterize the effect of two novel variants in HS patients on gene splicing to help minimize the rate of misdiagnosis of HS and enhance clinicians’ understanding of the disease. Participants and methods A retrospective review was conducted. Peripheral blood samples were collected from all the family members, and genomic DNA was extracted for genetic diagnostics. First, high-throughput sequencing technology was used for the preliminary screening of candidate causative variants. Thereafter, the variants were verified via Sanger sequencing. Furthermore, a pathogenicity analysis of the detected variants was performed including in silico prediction and in vitro experiments. We constructed matched wild-type and mutant-type minigene plasmid of ANK1 based on HEK293T cells to address the effects of variants on mRNA splicing. Results The c.1305 + 2 T > A (family1) and c.1305 + 2del (family2) variants were detected in the ANK1 gene. These two de novo mutations described by us which have not been reported prior to this study. Moreover, the validation results of splicing reporter systems revealed that the intronic mutations resulted in abnormal pre-mRNA splicing. Specifically, the minigene plasmid expressing the c.1305 + 2 T > A variant transcribed the two aberrant transcripts: r.1305_1306ins1305 + 1_1305 + 229 and r.1305_1306ins1305 + 1_1305 + 552. The minigene plasmid expressing c.1305 + 2del transcribed the two aberrant transcripts: r.1305_1306ins1305 + 1_1305 + 228 and r.1305_1306ins1305 + 1_1305 + 551. Conclusion The two de novo variants identified in the ANK1 gene were the genetic etiology of the probands with HS in our study. Our findings further enrich the HS genotype database and provide a basis for genetic counselling and molecular diagnosis.

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“…Though APC mutations may not be detected in 20 to 40% of FAP patients, genetic test is necessary, because FAP should be differentiated from MUTYH-associated polyposis (MAP, an autosomal recessive mode of inheritance caused by biallelic germline MUTYH mutations), polymerase proofreading-associated polyposis (an autosomal dominant mode of inheritance caused by pathogenic germline variants in the POLE or POLD1), and somatic APC mosaicism. 2 11 12 A flowchart of FAP diagnosis is shown in Fig. 1 .…”

Section: Manifestation and Diagnosis Of Fapmentioning

confidence: 99%

“…Familial adenomatous polyposis (FAP), one of the common HCRCs, accounting for 1% of all colorectal cancer (CRC), is an autosomal dominant disease. 2 It is primarily caused by germline adenomatous polyposis coli (APC) mutation, which is a tumor suppressed gene and located at 5q21-q22 locus. 3 APC can inhibit the initiation and development of CRC, while its mutations contribute in early adenoma creation leading to chromosomal instability.…”

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confidence: 99%

Update on Surgical Management of FAP

Zhang

2023

Clin Colon Rectal Surg

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Familial adenomatous polyposis (FAP) is an autosomal dominant disease caused by pathogenic germline adenomatous polyposis coli mutation, and characterized with multiple adenomas in the colon and the rectum. Various genetic variants have been confirmed to be associated with corresponding FAP phenotypes, which play important roles in the diagnosis and surgical treatment of FAP. Generally, proctocolectomy is recommended for FAP patients at the age of 20s. Exceptionally, for patients with attenuated FAP, high-risk of desmoid, chemoprevention therapy, or other circumstances, surgery can be postponed. With the wide application of minimal invasive surgery in colorectal cancer, laparoscopic, robotic surgery, and natural orifice specimen extraction are proved to be feasible for FAP patients, but high-level evidences are needed to confirm their safety and advantages. In the times of precise medicine, the surgical management of FAP should vary with individuals based on genotype, phenotype, and clinical practice. Therefore, in addition to innovation in surgical procedures, investigation in links between genetic features and phenotypes will be helpful to optimize the surgical management of FAP in the future.

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Paired Somatic-Germline Testing of 15 Polyposis and Colorectal Cancer–Predisposing Genes Highlights the Role of APC Mosaicism in de Novo Familial Adenomatous Polyposis

Cited by 11 publications

References 34 publications

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

Genome sequencing-based discovery of a novel deep intronic APC pathogenic variant causing exonization

De novo variations of ANK1 gene caused hereditary spherocytosis in two Chinese children by affecting pre-mRNA splicing

Update on Surgical Management of FAP

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