Clinical and Molecular Characterization of SMAD4 Splicing Variants in Patients with Juvenile Polyposis Syndrome.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Intestinal Polyposis*/genetics ; Intestinal Polyposis*/congenital ; Neoplastic Syndromes, Hereditary*/genetics ; RNA Splicing*/genetics ; Smad4 Protein*/genetics; Adult ; Female ; Humans ; Male ; Middle Aged ; Germ-Line Mutation ; Introns/genetics ; Pedigree

Juvenile polyposis syndrome (JPS) is an inherited autosomal dominant condition that predisposes to the development of juvenile polyps throughout the gastrointestinal (GI) tract, and it poses an increased risk of GI malignancy. Germline causative variants were identified in the SMAD4 gene in a subset (20%) of JPS cases. Most SMAD4 germline genetic variants published to date are missense, nonsense, and frameshift mutations. SMAD4 germline alterations predicted to result in aberrant splicing have rarely been reported. Here, we report two unrelated Italian families harboring two different SMAD4 intronic variants, c.424+5G>A and c.425-9A>G, which are clinically associated with colorectal cancer and/or juvenile GI polyps. In silico prediction analysis, in vitro minigene assays, and RT-PCR showed that the identified variants lead to aberrant SMAD4 splicing via the exonization of intronic nucleotides, resulting in a premature stop codon. This is expected to cause the production of a truncated protein. This study expands the landscape of SMAD4 germline genetic variants associated with GI polyposis and/or cancer. Moreover, it emphasizes the importance of the functional characterization of SMAD4 splicing variants through RNA analysis, which can provide new insights into genetic disease variant interpretation, enabling tailored genetic counseling, management, and surveillance of patients with GI polyposis and/or cancer.

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"Ricerca Corrente 2024-2026" to C.F. and V.D. Italian Ministry of Health; Ricerca Corrente 2023-2025" to V.G. Italian Ministry of Health; Ricerca Corrente 2024-2026 to C.S. Italian Ministry of Health; Starting Grant SG-2019-12371540 to P.S. Italian Ministry of Health; IG-23794 to C.S. Italian Association for Cancer Research (AIRC); ID26678-2021 AIRC Fellowship for Italy to M.L.S. Italian Association for Cancer Research (AIRC)

Keywords: SMAD4; juvenile polyposis syndrome; splicing variants; variant of uncertain significance

0 (Smad4 Protein)
0 (SMAD4 protein, human)

Juvenile polyposis syndrome

Date Created: 20240727 Date Completed: 20240727 Latest Revision: 20240813

20240813

PMC11276957

10.3390/ijms25147939

39063183