A progeroid syndrome caused by a deep intronic variant in TAPT1 is revealed by RNA/SI-NET sequencing

Area of Science:

• Genetics
• Molecular Biology
• Genomic Medicine

Background:

• Exome sequencing is crucial for identifying Mendelian disease-causing germline variations.
• Non-coding regions (98% of the genome) are often uncaptured by exome sequencing.
• RNA sequencing (RNA-seq) is vital for functional annotation of intronic and intergenic variants.

Purpose of the Study:

• To identify the genetic cause of recessive Osteogenesis Imperfecta (OI) and neonatal progeria syndrome in six patients.
• To demonstrate the utility of RNA-seq in diagnosing diseases linked to non-coding variants.
• To elucidate the molecular mechanisms underlying the identified disease.

Main Methods:

• Integration of homozygosity mapping and RNA-seq.
• Identification of a deep intronic TAPT1 mutation (c.1237-52 G>A).
• Utilized SI-NET-seq to analyze nascent transcription and pre-mRNA processing.
• Pathway analysis of collagen and extracellular matrix biology.

Main Results:

• A deep intronic TAPT1 mutation (c.1237-52 G>A) was identified and segregated with the disease.
• The mutation alters pre-mRNA processing, specifically enhancing exon 12 skipping of TAPT1.
• This splicing defect results in a protein-null allele.
• Dysregulation of collagen and extracellular matrix pathways was observed in patient cells.

Conclusions:

• Transcriptomic approaches are powerful for deciphering the impact of non-coding variants.
• The study highlights the molecular mechanisms of OI and neonatal progeria syndrome.
• RNA-seq is a critical companion diagnostic for identifying variants in non-coding regions.