Clinical characteristics and APC gene mutation spectrum of familial adenomatous polyposis patients in China

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Methods Comprehensive APC gene sequencing was conducted in 33 unrelated Chinese polyposis patients, with subsequent genotype-phenotype correlation analysis leveraging clinical data from index cases and affected relatives. Results Germline APC mutations were identified in 28/33 (84.8%) probands. Patients with profuse FAP developed polyposis and cancer significantly earlier than attenuated or intermediate subtypes (p T, c.1285delC, c.1350_1352delinsAC, c.3992_3993insA, c.230_233delTAGA, EX5_16DEL, Ex3_16DEL. Most intermediate FAP cases (92.9%, 13/14) had disease-causing mutations in codons 157–1595, matching the known mutation hotspot region. 100% (4/4) of congenital hypertrophy of retinal pigment epithelium, 75% (3/4) of gastroduodenal adenomas, and 50% (1/2) of desmoid tumor cases were localized to established APC risk domains. Conclusion Our comprehensive profiling of APC variants in Chinese polyposis patients delineated clinical characteristics and novel pathogenic mutations. Crucially, we observed divergent genotype-phenotype correlations in part of mutation-positive families, necessitating tailored genetic counseling and management strategies for this population. familial adenomatous polyposis APC mutation screening genotype-phenotype Figures Figure 1 Figure 2 Introduction Familial adenomatous polyposis (FAP) is a rare hereditary syndrome that significantly increases the risk of developing colorectal cancer (CRC)[ 1 ]. This condition is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, typically during the second decade of life[ 2 ]. FAP is subclassified into attenuated FAP (10–100 adenomas), intermediate FAP and profuse FAP (> 100 adenomas)[ 3 ]. FAP is inherited in an autosomal dominant manner, primarily due to mutations in the adenomatous polyposis coli (APC) gene located on chromosome 5q21[ 4 ]. Nearly all untreated patients progress to CRC without early identification and intervention. Defining the pathogenic APC variant within a family enables cascade genetic screening of presymptomatic at-risk relatives. Early identification of high-risk individuals from polyposis pedigrees is critical for reducing cancer-related morbidity. More than 3000 unique germline pathogenic mutations in the APC gene have been identified in individuals with FAP till now[ 5 ]. Existing literature supports genotype-phenotype correlations in FAP, where mutation localization influences disease manifestations[ 6 ]. Leveraging these correlations enhances diagnostic precision and surveillance strategies. Nevertheless, comprehensive clinical and genotypic profiling of Chinese FAP cohorts remains limited[ 5 ]. We conducted this study to establish the APC mutational landscape in Chinese FAP probands and systematically assess genotype-phenotype correlations. Method Patients 33 unrelated probands clinically suspected of adenomatous polyposis syndrome were enrolled at the Department of Colorectal Surgery, Tianjin Union Medical Center (Tianjin, China) between January 2010 and June 2023. Patients diagnosed with hamartomatous polyposis syndromes (e.g., juvenile polyposis syndrome, Peutz-Jeghers syndrome, or Cowden syndrome) were excluded. Detailed family history and medical records, encompassing pathologic, radiologic, and endoscopic data, were retrospectively reviewed across all families. Conducted by the Declaration of Helsinki, this study received approval from the ethics committee of Tianjin Union Medical Center, with informed consent obtained from all participants. Mutation and data analysis Peripheral blood samples from all patients underwent genomic DNA extraction with the QIAamp DNA Blood Mini Kit (Qiagen, Germany), adhering strictly to the manufacturer's protocol. DNA libraries were prepared from 30–50 ng input DNA using the NEBNext Ultra II FS DNA Library Prep Kit (New England BioLabs, Ipswich, MA, USA) with manufacturer-specified protocols. Target enrichment was performed with IDT xGen Lockdown Probes (Integrated DNA Technologies, Coralville, IA, USA), and final libraries (150 bp average insert size) underwent paired-end sequencing on an Illumina MGISEQ-2000 platform (BGI-Tianjin, China). Data were processed through MGI’s bioinformatic pipeline (SOAPnuke, BWA, GATK) for variant calling. Variant annotation was performed via ANNOVAR (v2019Oct24) with multipathogenicity validation across tiered databases: 1) Disease-specific repositories (InSiGHT, LOVD); 2) Clinical significance archives (ClinVar, HGMD Professional); and 3) Phenotype-genotype reference (OMIM). The novel mutations were named and referred according to the nomenclature used by the Human Genome Variation Society. Germline variants in Mendelian disorders received pathogenicity classifications ("pathogenic," "benign," or "uncertain significance") per ACMG/AMP guidelines. Novel variants were designated using Human Genome Variation Society (HGVS) nomenclature standards. Statistical analysis Normally distributed continuous variables are expressed as mean ± SD; non-normal variables as median (IQR). Categorical data are presented as counts (percentages). Means of 2 continuous normally distributed variables were compared by independent samples Student's T-test. The Mann-Whitney U test was used to compare the means of 2 groups of variables not normally distributed. All analyses were two-sided (significance threshold: α = 0.05) using GraphPad Prism v8 and R v3.6.1. Results Patient characteristics Table 1 summarizes the clinical characteristics of 33 FAP probands. The cohort comprised 19 (57.6%) males and 14 (42.4%) females. Family history was documented in 30 (90.9%) cases. Phenotypic classification revealed attenuated FAP in 8 patients (24.2%), intermediate FAP in 17 (51.5%), and profuse FAP in 8 (24.2%). Extraintestinal manifestations associated with FAP were observed in 13 (39.4%) patients, while carcinoma development was identified in 23 (69.7%). Germline APC mutations were detected in 28 (84.8%) probands. Polyposis/Cancer age at diagnosis The ages at polyposis and cancer onset in probands with different FAP subtypes were analyzed, as shown in Fig. 1. The median age of polyposis onset in APC-positive families was 37 (9) for attenuated FAP, 30 (8) for intermediate FAP, and 19.5 (6) for profuse FAP. Likewise, the median age of cancer onset was 55 (13.25) for attenuated FAP, 55 (6) for intermediate FAP, and 28 (15.5) for profuse FAP. Comparison among the three groups revealed that profuse FAP exhibited significantly earlier polyposis and cancer onset compared to attenuated FAP and intermediate FAP patients ( P < 0.05, Fig. 1). Mutations of the APC gene The mutation spectrum of the 28 probands with detectable APC variants was summarized in Table 2, excluding families 20, 21, 22, 32, and 33 where no mutations were identified. The 28 APC mutations consist of 15 (53.6%) frameshift, 7 (25.0%) nonsense, 3 (10.7%) splice-site mutation, 2 (7.1%)deletion, and 1 (3.6%) missense. 13 out of 35 mutations (46.4%) were localized within exon 15. Codon 1309 has the highest mutation frequency, reaching 2 cases, accounting for 7%(2/29) of the total APC gene mutation types in all FAP families. Moreover, 7 novel APC mutations were identified, including c.646-1 > T (Pedigree 1), c.1285delC (Pedigree 2), c.1350_1352delinsAC (Pedigree 3), c.3992_3993insA (Pedigree 18), c.230_233delTAGA (Pedigree 19), and large deletions (Pedigrees 12 and 15). Table 2 Spectrum of APC mutations in Chinese probands with familial adenomatous polyposis ID FAP type Coding exon/intron Nucleotide Protein Mutation type 1 Attenuated Intron6 c.646-1G > T --- Splice 2 Intermediate CDS9 c.1285delC p.Pro429Glnfs*25 Frameshift 3 Profuse CDS10 c.1350-1352delinsAC p.Cys451Leufs*3 Frameshift 4 Attenuated CDS3 c.289G > A p.Gly97Arg Frameshift 5 Intermediate CDS15 c.2393_2394insT p.Tyr799Leufs*4 Frameshift 6 Intermediate CDS15 c.3418delC p.Pro1140Leufs*25 Frameshift 7 Intermediate Intron14 c.1744-1G > A --- Splice 8 Intermediate CDS10 c.1238_1239insA p.Arg414Thr fs*5 Frameshift 9 Intermediate CDS15 c.3921_3925delAAAAG p.Glu1309Aspfs*4 Frameshift 10 Attenuated CDS5 c.531 + 2T > A --- Splice 11 Profuse CDS15 c.2413C > T p.Arg805Ter Nonsense 12 Intermediate EX5_16/CDS4_15 EX5_16DEL --- Deletion 13 Intermediate CDS4 c.474T > G p.Tyr158Ter Missense 14 Intermediate CDS15 c.3486T > A p.Tyr1162Ter Nonsense 15 Intermediate EX3_16/CDS3_15 Ex3_16DEL --- Deletion 16 Intermediate CDS15 c.3921_3925delAAAAG p.Ile13071lefs*6 Frameshift 17 Profuse CDS15 c.3921_3925delAAAAG p.Glu1309Aspfs*4 Frameshift 18 Profuse CDS15 c.3992_3993insA p.Thr1332Asnfs*10 Frameshift 19 Attenuated CDS3 c.230_233delTAGA p.Asp78Alafs*7 Frameshift 23 Intermediate CDS3 c.288T > G p.Tyr96* Nonsense 24 Profuse CDS15 c.2376_2379delGCAA p.Gln793Valfs*26 Frameshift 25 Intermediate CDS15 c.3596dupA p.Ser1200Glufs*8 Frameshift 26 Intermediate CDS13 c.1682delA p.Lys561Argfs*9 Frameshift 27 Profuse CDS5 c..637C > T p.Arg213* Nonsense 28 Intermediate CDS15 c.4348C > T p.Arg1450* Nonsense 29 Intermediate CDS13 c.1690C > T p.Arg564* Nonsense 30 Profuse CDS15 c.3921_3924delAAAA p.Ile1307Metfs*13 Frameshift 31 Intermediate CDS15 3183_3187delACAAA p.Gln1062* Nonsense Genotype-phenotype correlations Multiple studies confirm genotype–phenotype correlations in polyposis syndromes, with mutation location generally linked to clinical presentation despite some inconsistencies[3, 7]. Our cohort’s clinical and genetic profiles were benchmarked against APC codon boundaries established in Leoz et al. (2015)[3]. Among 5 attenuated FAP patients, pathogenic variants proximal to codon 157 were identified in 2 cases, while mutations between codons 157–1595 occurred in 3 cases (Table 3, Fig. 2a). The majority of intermediate FAP cases (13/14, 92.9%) harbored pathogenic variants between codons 157 and 1595, consistent with the well-established mutation cluster region reported in the literature (Table 3, Fig. 2a). Approximately 42.9% (3/7) of severe polyposis cases harbored germline pathogenic variants within codons 1250–1464 (Table 3, Fig. 2a). Table 3 Genotype-phenotype correlations in probands with familial adenomatous polyposis FAP type N Codons Attenuated 5 78, 97, 531, 646, 1450 Intermediate 16 158, 414, 429, 474, 561, 564, 799, 805, 1062, 1140, 1162, 1200, 1309, 1744, 5–16 exon deletion, 3–16 exon deletion Profuse 7 213, 451, 793, 805, 1307, 1309, 1332 Extracolonic manifestations have also been associated with specific APC mutations[3]. Table 4 and Fig. 2b delineate APC variant distributions in cases with extracolonic manifestations, benchmarking these against established genotype-phenotype correlations[3]. Eleven APC-mutated FAP families exhibited genotype-aligned extracolonic manifestations in 64% (9/11) of cases, while two osteoma presentations lacked prior documentation in medical literature. Congenital hypertrophy of retinal pigment epithelium (CHRPE) manifested in four families, all harboring APC variants within codons 311–1465. A solitary thyroid carcinoma case carried pathogenic variants at codons 140–1309. 75% (3/4) of gastroduodenal adenomas cases were localized to established APC risk domains (codons 564–1493), whereas 50% (1/2) of desmoid tumors (codons 1445–2011). Table 4 Genotype-phenotype correlations in FAP probands with extraintestinal manifestations Extraintestinal manifestations N Codons Gastroduodenal adenomas 4 561, 1162, 1332, 1744 Desmoid tumors 2 1332, 1744 Osteomas 2 1140, 1450 CRHPE 4 414, 646, 799, 805 Thyroid tumor 1 805 CHRPE, congenital hypertrophy of the retinal pigment epithelium; Discussion Globally curated germline mutation repositories (HGMD and LOVD) document > 1600 distinct APC pathogenic variants, with > 200 alterations specifically identified in Chinese populations ( http://www.genomed.org/lovd2/home.php?select_db=APC )[ 8 ]. APC germline variants demonstrate a diffuse genomic distribution, with predominant clustering in the 5' region of exon 15-designated the Mutation Cluster Region (MCR, codons 1286–1513)[ 9 ]. This locus harbors established mutational hotspots at codon 1309 (17% prevalence) and 1061 (11% frequency) relative to all pathogenic APC alterations[ 3 , 5 ]. This study identified primary variant localization within codons 230–2413, with 75.9% (22/29) of pathogenic APC variants occurring specifically in the mutation cluster region (codons 1286–1513) among FAP pedigrees, consistent with literature. Of these, codon 1309 has the highest mutation frequency, reaching 2 cases, accounting for 7%(2/29) of the total APC gene mutation types in all FAP families. In a multi-center cohort investigation of 680 FAP patients, 6.9% (47/680) harbored codon 1309 deletion mutations, confirming this locus as a mutation hotspot[ 10 ]. Codon 1309 variants correlate with severe polyposis, premature symptom onset, and, when untreated, accelerate colorectal cancer mortality by approximately 10 years relative to other FAP-associated mutations[ 11 ]. In this study, we identified 7 novel APC mutations, including c.646-1 > T (Pedigree 1), c.1285delC (Pedigree 2), c.1350_1352delinsAC (Pedigree 3), c.3992_3993insA (Pedigree 18), c.230_233delTAGA (Pedigree 19), and large deletions (Pedigrees 12 and 15). These variants may reflect population-specific genetic architecture in Chinese FAP patients, particularly distinct mutational spectra. In 1992, the first genotype-phenotype correlation was described[ 12 ]. Truncating variants within codons 1250–1464 demonstrated significant association with profuse colorectal polyposis (> 5,000 adenomas)[ 13 , 14 ]. Nevertheless, the association is not absolute. Walon et al. found 4 novel truncating variants between codons 1250–1464, but no profuse polyposis was identified[ 15 ]. In this study, we also found 4 profuse cases showed APC mutations except codons 1250–1464. Research studies implicated germline APC variants causing intermediate FAP phenotypes primarily localize to codons 157–1595 (exons 4–15), with notable exclusions at codons 312–412 and 1250–1464[ 10 , 16 ]. We found intermediate FAP cases predominantly (92.9%, 13/14) harbored causative variants within the mutation cluster region (codons 157–1595), confirming the established genotype-phenotype correlation. Attenuated FAP phenotypes associate with APC variants in three discrete regions: proximal 5' domains (exons 4–5), alternative exon 9 splicing sites, and distal 3' terminus, corroborating genotype-phenotype patterns reported by Spirio et al[ 17 ] and Soravia et al[ 18 ]. Extracolonic manifestations have also been linked to specific APC mutations, particularly those situated beyond codon 1400[ 3 ]. CHRPE, as the most common extracolonic manifestation of FAP, is linked to mutations located at codons 311–1465[ 13 , 19 ]. Four CHRPE cases in our cohort harbored variants precisely concordant with mutation sites documented in existing literature. Eccles et.al firstly reported a family with inherited multiple desmoid tumors lacking FAP colonic manifestations, attributed to a pathogenic APC variant at codon 1924[ 20 ]. Desmoid tumor pathogenesis is currently established to associate with pathogenic variants within the APC 3' terminus, particularly distal to codon 1400 (1445–2011)[ 3 , 21 ]. Upper gastrointestinal tumors frequently manifest in both classical and attenuated FAP, with gastric/duodenal polyps specifically associated with pathogenic variants affecting exon 4, codons 564–1493, or distal 3' regions proximal to codon 1395[ 22 ]. Thyroid tumorigenesis demonstrates a significant association with pathogenic APC variants mapping to codons 140–1309, encompassing critical 5' regulatory domains[ 23 ]. Genotype-phenotype relationships for other extracolonic manifestations lack consistent clinical confirmation till now. Despite established genotype-phenotype correlations, marked phenotypic heterogeneity occurs among individuals, including family members, indicating environmental interactions and/or modifier gene effects. A key limitation involves restricted pedigree ascertainment, wherein only 33 families underwent genetic screening with minimal subject enrollment per proband. That’s a challenge attributable to low public health literacy regarding FAP progression and prevention in China. Moreover, the unclear phenotypic impact of identified mutations limits genotype-based clinical predictions, precluding population-specific surveillance recommendations for Chinese carriers. Instead, individualized management should prioritize colonic phenotypes and family history over strict genotypic data, necessitating larger longitudinal cohort studies for refined guidelines. Conclusion In this comprehensive investigation of the APC mutation spectrum in Chinese polyposis patients, we identified the clinical characteristics of probands and several novel pathogenic variants. Notably, part of APC mutation-positive families exhibited genotype-phenotype correlations that diverged from conventional predictions, necessitating population-specific adaptation of genetic counseling and clinical management protocols. Declarations Author Contributions Conceptualization: Jiaqi Kang, Zhao Zhang; Methodology: Jiaqi Kang, Richeng Li, Chen Xu; Data curation: Jiaqi Kang, Mingsen Li, Yongjun Yu; Investigation: Jiaqi Kang, Richeng Li, Mingsen Li, Yongjun Yu; Formal analysis: Jiaqi Kang; Supervision: Xin Lin, Chen Xu, Yuwei Li, Zhao Zhang; Funding acquisition: Zhao Zhang; Writing-original draft Jiaqi Kang, Richeng Li; Writing-review&editing: Jiaqi Kang, Richeng Li, Xin Lin, Mingsen Li, Yongjun Yu, Chen Xu, Yuwei Li, Zhao Zhang. Acknowledgements The authors acknowledge the patients and families for their collaboration. Funding statement This study was financially supported by Tianjin Science and Technology Funding (21JCYBJC00300), Key Project of Traditional Chinese Medicine of Tianjin Health Commission (2022006) Conflict of interest The authors declare that they have no conflict of interest. Ethics statement Not applicable. Data availability statement The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions. References Half E, Bercovich D, Rozen P. Familial adenomatous polyposis Orphanet journal of rare diseases . 2009;4:22. Vasen HF, Möslein G, Alonso Aet al. . Guidelines for the clinical management of familial adenomatous polyposis (FAP) Gut . 2008;57:704-713. Leoz ML, Carballal S, Moreira L, Ocaña T, Balaguer F. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management The application of clinical genetics . 2015;8:95-107. Dinarvand P, Davaro EP, Doan JVet al. . Familial Adenomatous Polyposis Syndrome: An Update and Review of Extraintestinal Manifestations Archives of pathology & laboratory medicine . 2019;143:1382-1398. Li N, Kang Q, Yang Let al. . Clinical characterization and mutation spectrum in patients with familial adenomatous polyposis in China Journal of gastroenterology and hepatology . 2019;34:1497-1503. Bunyan DJ, Shea-Simonds J, Reck AC, Finnis D, Eccles DM. Genotype-phenotype correlations of new causative APC gene mutations in patients with familial adenomatous polyposis Journal of medical genetics . 1995;32:728-731; García-Lozano JR, Cordero C, Fernández-Suárez A, Encarnación M, Pizarro A, Núñez-Roldán A. APC germ-line mutations in southern Spanish patients with familial adenomatous polyposis: genotype-phenotype correlations and identification of eight novel mutations Genetic testing . 2005;9:37-40; Torrezan GT, da Silva FC, Santos EMet al. . Mutational spectrum of the APC and MUTYH genes and genotype-phenotype correlations in Brazilian FAP, AFAP, and MAP patients Orphanet journal of rare diseases . 2013;8:54. Newton KF, Mallinson EK, Bowen Jet al. . 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Walon C, Kartheuser A, Michils Get al. . Novel germline mutations in the APC gene and their phenotypic spectrum in familial adenomatous polyposis kindreds Human genetics . 1997;100:601-605. Pouya F, Mojtabanezhad Shariatpanahi A, Ghaffarzadegan Ket al. . A novel large germ line deletion in adenomatous polyposis coli (APC) gene associated with familial adenomatous polyposis Molecular genetics & genomic medicine . 2018;6:1031-1040. Spirio L, Olschwang S, Groden Jet al. . Alleles of the APC gene: an attenuated form of familial polyposis Cell . 1993;75:951-957. Soravia C, Berk T, Madlensky Let al. . Genotype-phenotype correlations in attenuated adenomatous polyposis coli American journal of human genetics . 1998;62:1290-1301. Davies DR, Armstrong JG, Thakker Net al. . Severe Gardner syndrome in families with mutations restricted to a specific region of the APC gene American journal of human genetics . 1995;57:1151-1158. Eccles DM, van der Luijt R, Breukel Cet al. . Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene American journal of human genetics . 1996;59:1193-1201. Santos M, Rocha A, Martins V, Santos M. Desmoid Tumours in Familial Adenomatous Polyposis: Review of 17 Patients from a Portuguese Tertiary Center Journal of clinical and diagnostic research : JCDR . 2016;10:Pc01-pc05; Shimamoto Y, Takeuchi Y, Ishiguro Set al. . Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis Cancer Sci . 2023;114:4596-4606. Nieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature Critical reviews in oncology/hematology . 2007;61:153-161. Groen EJ, Roos A, Muntinghe FLet al. . Extra-intestinal manifestations of familial adenomatous polyposis Annals of surgical oncology . 2008;15:2439-2450; Triggiani V, Angelo Giagulli V, Tafaro Aet al. . Differentiated thyroid carcinoma and intestinal polyposis syndromes Endocrine, metabolic & immune disorders drug targets . 2012;12:377-381. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7339521","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":502925743,"identity":"ba896782-fab7-4dc7-b6d8-2262813dd583","order_by":0,"name":"Jiaqi Kang","email":"","orcid":"","institution":"Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University","correspondingAuthor":false,"prefix":"","firstName":"Jiaqi","middleName":"","lastName":"Kang","suffix":""},{"id":502925744,"identity":"46157229-777b-4164-8995-9031d3db919e","order_by":1,"name":"Richeng Li","email":"","orcid":"","institution":"Nankai 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Zhang","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAwklEQVRIiWNgGAWjYDACCQY2hg8/bOT4mZkPPyBaC+PMnjRjyXa2NAOitTDzsB1KNDjPoyBBlA752e3PHs7gOZBgfJiHwYChxiaaoBbGOQfSDT5Y3MkzO8x74AHDsbTcBkJamCUSjknO4HlWbHaYL8GAseEwYS1sEolt0jxshxM3N/MYSBClhUcimQ2sZQMzsVokJNLYJEGBLHEYGMgJxPhFfkb6MwlwVPYfPvzgQ40NYS2oIIE05aNgFIyCUTAKcAEArII9AUOgRHwAAAAASUVORK5CYII=","orcid":"","institution":"Tianjin Union Medical Center, The First Affiliated Hospital of Nankai University","correspondingAuthor":true,"prefix":"","firstName":"Zhao","middleName":"","lastName":"Zhang","suffix":""}],"badges":[],"createdAt":"2025-08-10 14:53:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7339521/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7339521/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":89640359,"identity":"ee4e6133-5319-4072-9357-599f081d5765","added_by":"auto","created_at":"2025-08-22 08:04:33","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":447075,"visible":true,"origin":"","legend":"\u003cp\u003eAge of polyposis and cancer onset per group\u003c/p\u003e","description":"","filename":"Fig.1.png","url":"https://assets-eu.researchsquare.com/files/rs-7339521/v1/94f8de10020f6169fd8b3922.png"},{"id":89640352,"identity":"e3e164d0-c0b8-4725-a344-07ab997581a4","added_by":"auto","created_at":"2025-08-22 08:04:33","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":1047333,"visible":true,"origin":"","legend":"\u003cp\u003eGenotype-phenotype correlation.\u003c/p\u003e","description":"","filename":"Fig.2.png","url":"https://assets-eu.researchsquare.com/files/rs-7339521/v1/b3e008cc2b5543717773b4db.png"},{"id":91148190,"identity":"ab980c75-e880-4d71-b1ff-f374ab6b0853","added_by":"auto","created_at":"2025-09-12 06:43:29","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2269474,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7339521/v1/68382197-b003-4da5-92ef-94068eac03df.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical characteristics and APC gene mutation spectrum of familial adenomatous polyposis patients in China","fulltext":[{"header":"Introduction","content":"\u003cp\u003eFamilial adenomatous polyposis (FAP) is a rare hereditary syndrome that significantly increases the risk of developing colorectal cancer (CRC)[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. This condition is characterized by the development of hundreds to thousands of adenomatous polyps in the colon and rectum, typically during the second decade of life[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. FAP is subclassified into attenuated FAP (10\u0026ndash;100 adenomas), intermediate FAP and profuse FAP (\u0026gt;\u0026thinsp;100 adenomas)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. FAP is inherited in an autosomal dominant manner, primarily due to mutations in the adenomatous polyposis coli (APC) gene located on chromosome 5q21[\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Nearly all untreated patients progress to CRC without early identification and intervention. Defining the pathogenic APC variant within a family enables cascade genetic screening of presymptomatic at-risk relatives.\u003c/p\u003e\u003cp\u003eEarly identification of high-risk individuals from polyposis pedigrees is critical for reducing cancer-related morbidity. More than 3000 unique germline pathogenic mutations in the APC gene have been identified in individuals with FAP till now[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Existing literature supports genotype-phenotype correlations in FAP, where mutation localization influences disease manifestations[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Leveraging these correlations enhances diagnostic precision and surveillance strategies. Nevertheless, comprehensive clinical and genotypic profiling of Chinese FAP cohorts remains limited[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. We conducted this study to establish the APC mutational landscape in Chinese FAP probands and systematically assess genotype-phenotype correlations.\u003c/p\u003e"},{"header":"Method","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003ePatients\u003c/h2\u003e\u003cp\u003e33 unrelated probands clinically suspected of adenomatous polyposis syndrome were enrolled at the Department of Colorectal Surgery, Tianjin Union Medical Center (Tianjin, China) between January 2010 and June 2023. Patients diagnosed with hamartomatous polyposis syndromes (e.g., juvenile polyposis syndrome, Peutz-Jeghers syndrome, or Cowden syndrome) were excluded. Detailed family history and medical records, encompassing pathologic, radiologic, and endoscopic data, were retrospectively reviewed across all families. Conducted by the Declaration of Helsinki, this study received approval from the ethics committee of Tianjin Union Medical Center, with informed consent obtained from all participants.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eMutation and data analysis\u003c/h3\u003e\n\u003cp\u003ePeripheral blood samples from all patients underwent genomic DNA extraction with the QIAamp DNA Blood Mini Kit (Qiagen, Germany), adhering strictly to the manufacturer's protocol. DNA libraries were prepared from 30\u0026ndash;50 ng input DNA using the NEBNext Ultra II FS DNA Library Prep Kit (New England BioLabs, Ipswich, MA, USA) with manufacturer-specified protocols. Target enrichment was performed with IDT xGen Lockdown Probes (Integrated DNA Technologies, Coralville, IA, USA), and final libraries (150 bp average insert size) underwent paired-end sequencing on an Illumina MGISEQ-2000 platform (BGI-Tianjin, China). Data were processed through MGI\u0026rsquo;s bioinformatic pipeline (SOAPnuke, BWA, GATK) for variant calling. Variant annotation was performed via ANNOVAR (v2019Oct24) with multipathogenicity validation across tiered databases: 1) Disease-specific repositories (InSiGHT, LOVD); 2) Clinical significance archives (ClinVar, HGMD Professional); and 3) Phenotype-genotype reference (OMIM). The novel mutations were named and referred according to the nomenclature used by the Human Genome Variation Society. Germline variants in Mendelian disorders received pathogenicity classifications (\"pathogenic,\" \"benign,\" or \"uncertain significance\") per ACMG/AMP guidelines. Novel variants were designated using Human Genome Variation Society (HGVS) nomenclature standards.\u003c/p\u003e\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\u003ch2\u003eStatistical analysis\u003c/h2\u003e\u003cp\u003eNormally distributed continuous variables are expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD; non-normal variables as median (IQR). Categorical data are presented as counts (percentages). Means of 2 continuous normally distributed variables were compared by independent samples Student's T-test. The Mann-Whitney U test was used to compare the means of 2 groups of variables not normally distributed. All analyses were two-sided (significance threshold: α\u0026thinsp;=\u0026thinsp;0.05) using GraphPad Prism v8 and R v3.6.1.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec7\"\u003e\n \u003ch2\u003ePatient characteristics\u003c/h2\u003e\n \u003cp\u003eTable\u0026nbsp;1 summarizes the clinical characteristics of 33 FAP probands. The cohort comprised 19 (57.6%) males and 14 (42.4%) females. Family history was documented in 30 (90.9%) cases. Phenotypic classification revealed attenuated FAP in 8 patients (24.2%), intermediate FAP in 17 (51.5%), and profuse FAP in 8 (24.2%). Extraintestinal manifestations associated with FAP were observed in 13 (39.4%) patients, while carcinoma development was identified in 23 (69.7%). Germline APC mutations were detected in 28 (84.8%) probands.\u003c/p\u003e\n \u003cdiv\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec8\"\u003e\n \u003ch2\u003ePolyposis/Cancer age at diagnosis\u003c/h2\u003e\n \u003cp\u003eThe ages at polyposis and cancer onset in probands with different FAP subtypes were analyzed, as shown in Fig.\u0026nbsp;1. The median age of polyposis onset in APC-positive families was 37 (9) for attenuated FAP, 30 (8) for intermediate FAP, and 19.5 (6) for profuse FAP. Likewise, the median age of cancer onset was 55 (13.25) for attenuated FAP, 55 (6) for intermediate FAP, and 28 (15.5) for profuse FAP. Comparison among the three groups revealed that profuse FAP exhibited significantly earlier polyposis and cancer onset compared to attenuated FAP and intermediate FAP patients (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.05, Fig.\u0026nbsp;1).\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eMutations of the APC gene\u003c/h3\u003e\n\u003cp\u003eThe mutation spectrum of the 28 probands with detectable APC variants was summarized in Table\u0026nbsp;2, excluding families 20, 21, 22, 32, and 33 where no mutations were identified. The 28 APC mutations consist of 15 (53.6%) frameshift, 7 (25.0%) nonsense, 3 (10.7%) splice-site mutation, 2 (7.1%)deletion, and 1 (3.6%) missense. 13 out of 35 mutations (46.4%) were localized within exon 15. Codon 1309 has the highest mutation frequency, reaching 2 cases, accounting for 7%(2/29) of the total APC gene mutation types in all FAP families. Moreover, 7 novel APC mutations were identified, including c.646-1 \u0026gt; T (Pedigree 1), c.1285delC (Pedigree 2), c.1350_1352delinsAC (Pedigree 3), c.3992_3993insA (Pedigree 18), c.230_233delTAGA (Pedigree 19), and large deletions (Pedigrees 12 and 15).\u003c/p\u003e\u003cp\u003e\u003cimg 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\"\u003e\u003c/p\u003e\n\n\u003cdiv\u003e\n \u003ctable id=\"Tab2\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 2\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eSpectrum of APC mutations in Chinese probands with familial adenomatous polyposis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFAP type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCoding exon/intron\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eNucleotide\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eProtein\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMutation type\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttenuated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntron6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.646-1G \u0026gt; T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSplice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.1285delC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Pro429Glnfs*25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.1350-1352delinsAC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Cys451Leufs*3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttenuated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.289G \u0026gt; A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Gly97Arg\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.2393_2394insT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Tyr799Leufs*4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3418delC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Pro1140Leufs*25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntron14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.1744-1G \u0026gt; A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSplice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.1238_1239insA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Arg414Thr fs*5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3921_3925delAAAAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Glu1309Aspfs*4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttenuated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.531 + 2T \u0026gt; A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSplice\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.2413C \u0026gt; T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Arg805Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEX5_16/CDS4_15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEX5_16DEL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.474T \u0026gt; G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Tyr158Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMissense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e14\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3486T \u0026gt; A\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Tyr1162Ter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEX3_16/CDS3_15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEx3_16DEL\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e---\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDeletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3921_3925delAAAAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Ile13071lefs*6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3921_3925delAAAAG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Glu1309Aspfs*4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3992_3993insA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Thr1332Asnfs*10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e19\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttenuated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.230_233delTAGA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Asp78Alafs*7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.288T \u0026gt; G\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Tyr96*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e24\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.2376_2379delGCAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Gln793Valfs*26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3596dupA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Ser1200Glufs*8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e26\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.1682delA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Lys561Argfs*9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec..637C \u0026gt; T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Arg213*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.4348C \u0026gt; T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Arg1450*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e29\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.1690C \u0026gt; T\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Arg564*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ec.3921_3924delAAAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Ile1307Metfs*13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eFrameshift\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e31\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCDS15\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e3183_3187delACAAA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003ep.Gln1062*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNonsense\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003ch3\u003eGenotype-phenotype correlations\u003c/h3\u003e\n\u003cp\u003eMultiple studies confirm genotype–phenotype correlations in polyposis syndromes, with mutation location generally linked to clinical presentation despite some inconsistencies[3, 7]. Our cohort’s clinical and genetic profiles were benchmarked against APC codon boundaries established in Leoz et al. (2015)[3]. Among 5 attenuated FAP patients, pathogenic variants proximal to codon 157 were identified in 2 cases, while mutations between codons 157–1595 occurred in 3 cases (Table\u0026nbsp;3, Fig.\u0026nbsp;2a). The majority of intermediate FAP cases (13/14, 92.9%) harbored pathogenic variants between codons 157 and 1595, consistent with the well-established mutation cluster region reported in the literature (Table\u0026nbsp;3, Fig.\u0026nbsp;2a). Approximately 42.9% (3/7) of severe polyposis cases harbored germline pathogenic variants within codons 1250–1464 (Table\u0026nbsp;3, Fig.\u0026nbsp;2a).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab3\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 3\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eGenotype-phenotype correlations in probands with familial adenomatous polyposis\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eFAP type\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCodons\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAttenuated\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e78, 97, 531, 646, 1450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eIntermediate\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e158, 414, 429, 474, 561, 564, 799, 805, 1062, 1140, 1162, 1200, 1309, 1744, 5–16 exon deletion, 3–16 exon deletion\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eProfuse\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e213, 451, 793, 805, 1307, 1309, 1332\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003eExtracolonic manifestations have also been associated with specific APC mutations[3]. Table\u0026nbsp;4 and Fig.\u0026nbsp;2b delineate APC variant distributions in cases with extracolonic manifestations, benchmarking these against established genotype-phenotype correlations[3]. Eleven APC-mutated FAP families exhibited genotype-aligned extracolonic manifestations in 64% (9/11) of cases, while two osteoma presentations lacked prior documentation in medical literature. Congenital hypertrophy of retinal pigment epithelium (CHRPE) manifested in four families, all harboring APC variants within codons 311–1465. A solitary thyroid carcinoma case carried pathogenic variants at codons 140–1309. 75% (3/4) of gastroduodenal adenomas cases were localized to established APC risk domains (codons 564–1493), whereas 50% (1/2) of desmoid tumors (codons 1445–2011).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eGenotype-phenotype correlations in FAP probands with extraintestinal manifestations\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eExtraintestinal manifestations\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eN\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eCodons\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGastroduodenal adenomas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e561, 1162, 1332, 1744\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDesmoid tumors\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1332, 1744\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eOsteomas\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1140, 1450\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCRHPE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e414, 646, 799, 805\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eThyroid tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e805\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003ctfoot\u003e\n \u003ctr\u003e\n \u003ctd colspan=\"3\"\u003eCHRPE, congenital hypertrophy of the retinal pigment epithelium;\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tfoot\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eGlobally curated germline mutation repositories (HGMD and LOVD) document\u0026thinsp;\u0026gt;\u0026thinsp;1600 distinct APC pathogenic variants, with \u0026gt;\u0026thinsp;200 alterations specifically identified in Chinese populations (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://www.genomed.org/lovd2/home.php?select_db=APC\u003c/span\u003e\u003cspan address=\"http://www.genomed.org/lovd2/home.php?select_db=APC\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e)[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. APC germline variants demonstrate a diffuse genomic distribution, with predominant clustering in the 5' region of exon 15-designated the Mutation Cluster Region (MCR, codons 1286\u0026ndash;1513)[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. This locus harbors established mutational hotspots at codon 1309 (17% prevalence) and 1061 (11% frequency) relative to all pathogenic APC alterations[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. This study identified primary variant localization within codons 230\u0026ndash;2413, with 75.9% (22/29) of pathogenic APC variants occurring specifically in the mutation cluster region (codons 1286\u0026ndash;1513) among FAP pedigrees, consistent with literature. Of these, codon 1309 has the highest mutation frequency, reaching 2 cases, accounting for 7%(2/29) of the total APC gene mutation types in all FAP families. In a multi-center cohort investigation of 680 FAP patients, 6.9% (47/680) harbored codon 1309 deletion mutations, confirming this locus as a mutation hotspot[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Codon 1309 variants correlate with severe polyposis, premature symptom onset, and, when untreated, accelerate colorectal cancer mortality by approximately 10 years relative to other FAP-associated mutations[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In this study, we identified 7 novel APC mutations, including c.646-1\u0026thinsp;\u0026gt;\u0026thinsp;T (Pedigree 1), c.1285delC (Pedigree 2), c.1350_1352delinsAC (Pedigree 3), c.3992_3993insA (Pedigree 18), c.230_233delTAGA (Pedigree 19), and large deletions (Pedigrees 12 and 15). These variants may reflect population-specific genetic architecture in Chinese FAP patients, particularly distinct mutational spectra.\u003c/p\u003e\u003cp\u003eIn 1992, the first genotype-phenotype correlation was described[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Truncating variants within codons 1250\u0026ndash;1464 demonstrated significant association with profuse colorectal polyposis (\u0026gt;\u0026thinsp;5,000 adenomas)[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Nevertheless, the association is not absolute. Walon et al. found 4 novel truncating variants between codons 1250\u0026ndash;1464, but no profuse polyposis was identified[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. In this study, we also found 4 profuse cases showed APC mutations except codons 1250\u0026ndash;1464. Research studies implicated germline APC variants causing intermediate FAP phenotypes primarily localize to codons 157\u0026ndash;1595 (exons 4\u0026ndash;15), with notable exclusions at codons 312\u0026ndash;412 and 1250\u0026ndash;1464[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. We found intermediate FAP cases predominantly (92.9%, 13/14) harbored causative variants within the mutation cluster region (codons 157\u0026ndash;1595), confirming the established genotype-phenotype correlation. Attenuated FAP phenotypes associate with APC variants in three discrete regions: proximal 5' domains (exons 4\u0026ndash;5), alternative exon 9 splicing sites, and distal 3' terminus, corroborating genotype-phenotype patterns reported by Spirio et al[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e] and Soravia et al[\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eExtracolonic manifestations have also been linked to specific APC mutations, particularly those situated beyond codon 1400[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. CHRPE, as the most common extracolonic manifestation of FAP, is linked to mutations located at codons 311\u0026ndash;1465[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Four CHRPE cases in our cohort harbored variants precisely concordant with mutation sites documented in existing literature. Eccles et.al firstly reported a family with inherited multiple desmoid tumors lacking FAP colonic manifestations, attributed to a pathogenic APC variant at codon 1924[\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. Desmoid tumor pathogenesis is currently established to associate with pathogenic variants within the APC 3' terminus, particularly distal to codon 1400 (1445\u0026ndash;2011)[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Upper gastrointestinal tumors frequently manifest in both classical and attenuated FAP, with gastric/duodenal polyps specifically associated with pathogenic variants affecting exon 4, codons 564\u0026ndash;1493, or distal 3' regions proximal to codon 1395[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. Thyroid tumorigenesis demonstrates a significant association with pathogenic APC variants mapping to codons 140\u0026ndash;1309, encompassing critical 5' regulatory domains[\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. Genotype-phenotype relationships for other extracolonic manifestations lack consistent clinical confirmation till now.\u003c/p\u003e\u003cp\u003eDespite established genotype-phenotype correlations, marked phenotypic heterogeneity occurs among individuals, including family members, indicating environmental interactions and/or modifier gene effects. A key limitation involves restricted pedigree ascertainment, wherein only 33 families underwent genetic screening with minimal subject enrollment per proband. That\u0026rsquo;s a challenge attributable to low public health literacy regarding FAP progression and prevention in China. Moreover, the unclear phenotypic impact of identified mutations limits genotype-based clinical predictions, precluding population-specific surveillance recommendations for Chinese carriers. Instead, individualized management should prioritize colonic phenotypes and family history over strict genotypic data, necessitating larger longitudinal cohort studies for refined guidelines.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this comprehensive investigation of the APC mutation spectrum in Chinese polyposis patients, we identified the clinical characteristics of probands and several novel pathogenic variants. Notably, part of APC mutation-positive families exhibited genotype-phenotype correlations that diverged from conventional predictions, necessitating population-specific adaptation of genetic counseling and clinical management protocols.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAuthor Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eConceptualization: Jiaqi Kang, Zhao Zhang; Methodology: Jiaqi Kang, Richeng Li, Chen Xu; Data curation: Jiaqi Kang, Mingsen Li, Yongjun Yu; Investigation: Jiaqi Kang, Richeng Li, Mingsen Li, Yongjun Yu; Formal analysis: Jiaqi Kang; Supervision: Xin Lin, Chen Xu, Yuwei Li, Zhao Zhang; Funding acquisition: Zhao Zhang; Writing-original draft\u0026nbsp;\u0026nbsp;Jiaqi Kang, Richeng Li; Writing-review\u0026amp;editing: Jiaqi Kang, Richeng Li, Xin Lin, Mingsen Li, Yongjun Yu, Chen Xu, Yuwei Li, Zhao Zhang.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors acknowledge the patients and families for their collaboration.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was financially supported by Tianjin Science and Technology Funding (21JCYBJC00300), Key Project of Traditional Chinese Medicine of Tianjin Health Commission (2022006)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHalf E, Bercovich D, Rozen P. Familial adenomatous polyposis \u003cem\u003eOrphanet journal of rare diseases\u003c/em\u003e. 2009;4:22.\u003c/li\u003e\n\u003cli\u003eVasen HF, M\u0026ouml;slein G, Alonso Aet al. . Guidelines for the clinical management of familial adenomatous polyposis (FAP) \u003cem\u003eGut\u003c/em\u003e. 2008;57:704-713.\u003c/li\u003e\n\u003cli\u003eLeoz ML, Carballal S, Moreira L, Oca\u0026ntilde;a T, Balaguer F. The genetic basis of familial adenomatous polyposis and its implications for clinical practice and risk management \u003cem\u003eThe application of clinical genetics\u003c/em\u003e. 2015;8:95-107.\u003c/li\u003e\n\u003cli\u003eDinarvand P, Davaro EP, Doan JVet al. . 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Adenomatous Polyposis Coli Gene Mutations in 22 Chinese Pedigrees with Familial Adenomatous Polyposis \u003cem\u003eMedical science monitor : international medical journal of experimental and clinical research\u003c/em\u003e. 2019;25:3796-3803.\u003c/li\u003e\n\u003cli\u003eJung SM, Yoon YS, Lim SB, Yu CS, Kim JC. Clinicopathological features of familial adenomatous polyposis in Korean patients \u003cem\u003eWorld journal of gastroenterology\u003c/em\u003e. 2016;22:4380-4388; Schirosi L, Pellegrino M, Tarantino P, Mauro S, Tinelli A, Greco M. A new germline stop codon mutation in exon 15 of the APC gene predisposing to familial adenomatous polyposis \u003cem\u003eThe International journal of biological markers\u003c/em\u003e. 2013;28:e405-408.\u003c/li\u003e\n\u003cli\u003eFriedl W, Caspari R, Sengteller Met al. . Can APC mutation analysis contribute to therapeutic decisions in familial adenomatous polyposis? Experience from 680 FAP families \u003cem\u003eGut\u003c/em\u003e. 2001;48:515-521.\u003c/li\u003e\n\u003cli\u003eCaspari R, Friedl W, Mandl Met al. . Familial adenomatous polyposis: mutation at codon 1309 and early onset of colon cancer \u003cem\u003eLancet (London, England)\u003c/em\u003e. 1994;343:629-632; Gebert JF, Dupon C, Kadmon Met al. . Combined molecular and clinical approaches for the identification of families with familial adenomatous polyposis coli \u003cem\u003eAnnals of surgery\u003c/em\u003e. 1999;229:350-361.\u003c/li\u003e\n\u003cli\u003eNagase H, Miyoshi Y, Horii Aet al. . Correlation between the location of germ-line mutations in the APC gene and the number of colorectal polyps in familial adenomatous polyposis patients \u003cem\u003eCancer research\u003c/em\u003e. 1992;52:4055-4057.\u003c/li\u003e\n\u003cli\u003eEnomoto M, Konishi M, Iwama T, Utsunomiya J, Sugihara KI, Miyaki M. The relationship between frequencies of extracolonic manifestations and the position of APC germline mutation in patients with familial adenomatous polyposis \u003cem\u003eJapanese journal of clinical oncology\u003c/em\u003e. 2000;30:82-88.\u003c/li\u003e\n\u003cli\u003eFicari F, Cama A, Valanzano Ret al. . APC gene mutations and colorectal adenomatosis in familial adenomatous polyposis \u003cem\u003eBritish journal of cancer\u003c/em\u003e. 2000;82:348-353.\u003c/li\u003e\n\u003cli\u003eWalon C, Kartheuser A, Michils Get al. . Novel germline mutations in the APC gene and their phenotypic spectrum in familial adenomatous polyposis kindreds \u003cem\u003eHuman genetics\u003c/em\u003e. 1997;100:601-605.\u003c/li\u003e\n\u003cli\u003ePouya F, Mojtabanezhad Shariatpanahi A, Ghaffarzadegan Ket al. . 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Hereditary desmoid disease due to a frameshift mutation at codon 1924 of the APC gene \u003cem\u003eAmerican journal of human genetics\u003c/em\u003e. 1996;59:1193-1201.\u003c/li\u003e\n\u003cli\u003eSantos M, Rocha A, Martins V, Santos M. Desmoid Tumours in Familial Adenomatous Polyposis: Review of 17 Patients from a Portuguese Tertiary Center \u003cem\u003eJournal of clinical and diagnostic research : JCDR\u003c/em\u003e. 2016;10:Pc01-pc05; Shimamoto Y, Takeuchi Y, Ishiguro Set al. . Genotype-phenotype correlation for extracolonic aggressive phenotypes in patients with familial adenomatous polyposis \u003cem\u003eCancer Sci\u003c/em\u003e. 2023;114:4596-4606.\u003c/li\u003e\n\u003cli\u003eNieuwenhuis MH, Vasen HF. Correlations between mutation site in APC and phenotype of familial adenomatous polyposis (FAP): a review of the literature \u003cem\u003eCritical reviews in oncology/hematology\u003c/em\u003e. 2007;61:153-161.\u003c/li\u003e\n\u003cli\u003eGroen EJ, Roos A, Muntinghe FLet al. . Extra-intestinal manifestations of familial adenomatous polyposis \u003cem\u003eAnnals of surgical oncology\u003c/em\u003e. 2008;15:2439-2450; Triggiani V, Angelo Giagulli V, Tafaro Aet al. . Differentiated thyroid carcinoma and intestinal polyposis syndromes \u003cem\u003eEndocrine, metabolic \u0026amp; immune disorders drug targets\u003c/em\u003e. 2012;12:377-381.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"familial adenomatous polyposis, APC, mutation screening, genotype-phenotype","lastPublishedDoi":"10.21203/rs.3.rs-7339521/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7339521/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e\u003cp\u003eGiven the limited clinical and molecular characterization of familial adenomatous polyposis (FAP) in Chinese populations, this study delineates the APC mutational landscape in national probands and correlates genotypic profiles with phenotypic manifestations.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eComprehensive APC gene sequencing was conducted in 33 unrelated Chinese polyposis patients, with subsequent genotype-phenotype correlation analysis leveraging clinical data from index cases and affected relatives.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eGermline APC mutations were identified in 28/33 (84.8%) probands. Patients with profuse FAP developed polyposis and cancer significantly earlier than attenuated or intermediate subtypes (p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). 13 out of 35 mutations (46.4%) were localized within exon 15. Codon 1309 has the highest mutation frequency(7%,2/29). 7 novel APC mutations were identified, including c.646-1\u0026thinsp;\u0026gt;\u0026thinsp;T, c.1285delC, c.1350_1352delinsAC, c.3992_3993insA, c.230_233delTAGA, EX5_16DEL, Ex3_16DEL. Most intermediate FAP cases (92.9%, 13/14) had disease-causing mutations in codons 157\u0026ndash;1595, matching the known mutation hotspot region. 100% (4/4) of congenital hypertrophy of retinal pigment epithelium, 75% (3/4) of gastroduodenal adenomas, and 50% (1/2) of desmoid tumor cases were localized to established APC risk domains.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e\u003cp\u003eOur comprehensive profiling of APC variants in Chinese polyposis patients delineated clinical characteristics and novel pathogenic mutations. Crucially, we observed divergent genotype-phenotype correlations in part of mutation-positive families, necessitating tailored genetic counseling and management strategies for this population.\u003c/p\u003e","manuscriptTitle":"Clinical characteristics and APC gene mutation spectrum of familial adenomatous polyposis patients in China","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-22 08:04:28","doi":"10.21203/rs.3.rs-7339521/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b27dfd5f-1ffc-4d95-be9d-44b70ab7e21e","owner":[],"postedDate":"August 22nd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T05:23:46+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-22 08:04:28","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7339521","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7339521","identity":"rs-7339521","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}