Identification of coding exon 3 duplication in the BMPR1A gene in a patient with juvenile polyposis syndrome

Area of Science:

• Genetics
• Molecular Biology
• Gastroenterology

Background:

• Juvenile polyposis syndrome (JPS) is an inherited disorder with multiple gastrointestinal polyps and increased cancer risk.
• Germline mutations in BMPR1A and SMAD4 are known causes of JPS.
• The genetic basis of JPS is not fully understood, necessitating further investigation into novel mutations.

Purpose of the Study:

• To identify and characterize novel genetic mutations in patients diagnosed with Juvenile Polyposis Syndrome.
• To investigate the molecular mechanism underlying a newly identified BMPR1A gene mutation.
• To report the first documented case of a partial duplication in the BMPR1A gene associated with JPS.

Main Methods:

• Genetic analysis using Multiple Ligation Dependent Probe Amplification (MLPA) to detect copy number variations.
• Sanger sequencing to confirm the identified mutation and analyze the breakpoint region.
• In silico analysis to predict the functional impact of the identified mutation.

Main Results:

• A novel partial duplication of coding exon 3 in the BMPR1A gene (c.230+452_333+441dup1995) was identified in a JPS patient.
• The duplication resulted in a frameshift mutation, leading to a truncated BMPR1A protein (p.D112NfsX2), predicted to be pathogenic.
• The duplication breakpoint analysis revealed the involvement of Alu sequences, suggesting recombination as the mechanism of mutation.

Conclusions:

• The identified partial duplication in the BMPR1A gene is a novel pathogenic mutation causing Juvenile Polyposis Syndrome.
• Recombination between Alu sequences is implicated as the mechanism for this specific BMPR1A gene duplication.
• This finding expands the spectrum of BMPR1A mutations associated with JPS and highlights the importance of investigating copy number variations.