RNA Analysis Uncovers Pathogenic PARN Variant in Dyskeratosis Congenita

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Dyskeratosis congenita (DC) is a rare genetic disorder linked to telomere maintenance defects.
• DC presents with varied symptoms including bone marrow failure and mucocutaneous issues.
• This case involves a patient with atypical DC features like microcephaly and developmental delay.

Purpose of the Study:

• To investigate the genetic cause of atypical Dyskeratosis congenita in a 14-year-old male.
• To characterize a novel intronic variant in the PARN gene.
• To demonstrate the utility of whole-genome sequencing (WGS) and functional RNA analysis in diagnosing complex genetic disorders.

Main Methods:

• Whole-genome sequencing (WGS) was performed to identify genetic variants.
• Functional RNA analysis was conducted to assess the impact of identified variants.
• RNA studies evaluated exon skipping and nonsense-mediated decay (NMD).

Main Results:

• Two PARN gene variants were identified: a known pathogenic missense variant and a novel intronic variant (c.178-28T>C).
• The intronic variant disrupted RNA splicing, causing exon 4 skipping and NMD.
• This confirmed the pathogenicity of the novel intronic variant.

Conclusions:

• The novel intronic PARN variant is pathogenic and contributes to Dyskeratosis congenita.
• Functional validation is crucial for interpreting noncoding variants in genetic disorders.
• This expands the known genetic and clinical spectrum of PARN-related DC.