Phenotypic diversity among juvenile polyposis syndrome patients from different ethnic background

Katz, Lior H.; Gingold‐Belfer, Rachel; Hegger, Shani; Laish, Ido; Derazne, Estela; Weintraub, Ilana; Reznick-Levi, Gili; Goldberg, Yael; Levi, Zohar; Cohen, Shlomi; Half, Elizabeth E.

doi:10.1186/s13053-021-00207-9

Cited by 5 publications

(4 citation statements)

References 23 publications

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“…Variations in the number, size, and location of the polyps in the colon can be caused by different genetic mutations. For instance, people with JPS accompanied by Smad4 gene mutations typically have more polyps than people with JPS accompanied by BMPR1A gene mutations [16,17].…”

Section: Introductionmentioning

confidence: 99%

Studying the Effect of Host Genetic Background of Juvenile Polyposis Development using Collaborative Cross and Smad4 Knock-out Mouse Models

Zohud,

Midlej,

Lone

et al. 2024

Preprint

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Juvenile Polyposis Syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knockout on the development of intestinal polyps using Collaborative Cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knockout mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knockout males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knockout, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-Nearest Neighbours and Linear Regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides a comprehensive understanding of the intricate genetic interplay in the context of Smad4 knockout, offering valuable insights into potential therapeutic targets for juvenile polyposis and related diseases.

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Section: Introductionmentioning

confidence: 99%

Studying the Effect of Host Genetic Background of Juvenile Polyposis Development using Collaborative Cross and Smad4 Knock-out Mouse Models

Zohud,

Midlej,

Lone

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…The specific genetic mutations associated with the disorder can contribute to variations observed in juvenile polyposis syndrome (JPS), affecting the number, size, and location of polyps in the colon. For instance, people with JPS accompanied by Smad4 gene mutations typically have more polyps than people with JPS accompanied by BMPR 1 A gene mutations [ 9 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models

Zohud,

Midlej,

Lone

et al. 2024

IJMS

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Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.

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“…6 There are limited data on a genotype-phenotype correlation in JPS. 7 Patients with a SMAD4 DCV are at a greater risk of severe gastric polyposis, gastric malignancy, and hereditary hemorrhagic telangiectasia (HHT). 3,8 Data on clinical and endoscopic differences between DCV-positive and DCV-negative patients with JPS are limited.…”

Section: Introductionmentioning

confidence: 99%

“…There are limited data on a genotype‐phenotype correlation in JPS 7 . Patients with a SMAD4 DCV are at a greater risk of severe gastric polyposis, gastric malignancy, and hereditary hemorrhagic telangiectasia (HHT) 3,8 .…”

Section: Introductionmentioning

confidence: 99%

Juvenile polyposis syndrome in children: The impact of SMAD4 and BMPR1A mutations on clinical phenotype and polyp burden

Cohen,

Yerushalmy‐Feler,

Rojas

et al. 2024

J. pediatr. gastroenterol. nutr.

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ObjectiveA constitutional disease‐causing variant (DCV) in the SMAD4 or BMPR1A genes is present in 40%–60% of patients with juvenile polyposis syndrome (JPS). The aim of this study was to characterize the clinical course and polyp burden in children with DCV‐positive JPS compared to DCV‐negative JPS.MethodsDemographic, clinical, genetic, and endoscopic data of children with JPS were compiled from eight international centers in the ESPHGAN/NASPGHAN polyposis working group.ResultsA total of 124 children with JPS were included: 69 (56%) DCV‐negative and 55 (44%) DCV‐positive (53% SMAD4 and 47% BMPR1A) with a median (interquartile range [IQR]) follow‐up of 4 (2.8–6.4) years. DCV‐positive children were diagnosed at an older age compared to DCV‐negative children [12 (8–15.7) years vs. 5 (4–7) years, respectively, p < 0.001], had a higher frequency of family history of polyposis syndromes (50.9% vs. 1.4%, p < 0.001), experienced a greater frequency of extraintestinal manifestations (27.3% vs. 5.8%, p < 0.001), and underwent more gastrointestinal surgeries (16.4% vs. 1.4%, p = 0.002). The incidence rate ratio for the development of new colonic polyps was 6.15 (95% confidence interval 3.93–9.63, p < 0.001) in the DCV‐positive group compared to the DCV‐negative group, with an average of 12.2 versus 2 new polyps for every year of follow‐up. There was no difference in the burden of polyps between patients with SMAD4 and BMPR1A mutations.ConclusionsThis largest international cohort of pediatric JPS revealed that DCV‐positive and DCV‐negative children exhibit distinct clinical phenotype. These findings suggest a potential need of differentiated surveillance strategies based upon mutation status.

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Phenotypic diversity among juvenile polyposis syndrome patients from different ethnic background

Cited by 5 publications

References 23 publications

Studying the Effect of Host Genetic Background of Juvenile Polyposis Development using Collaborative Cross and Smad4 Knock-out Mouse Models

Studying the Effect of Host Genetic Background of Juvenile Polyposis Development using Collaborative Cross and Smad4 Knock-out Mouse Models

Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models

Juvenile polyposis syndrome in children: The impact of SMAD4 and BMPR1A mutations on clinical phenotype and polyp burden

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