Transcriptome sequencing identifies a noncoding, deep intronic variant in CLCN7 causing autosomal recessive...

Area of Science:

• Genetics
• Molecular Biology
• Rare Diseases

Background:

• Over 50% of children with rare genetic diseases remain undiagnosed.
• Standard clinical evaluation and DNA sequencing often fail to identify causative variants.
• Undiagnosed Diseases Programs utilize advanced techniques like transcriptome sequencing.

Observation:

• A child with severe infantile osteopetrosis presented with cranial nerve palsies, bone deformities, and bone marrow failure.
• Whole-genome sequencing did not yield a diagnosis for this patient.
• Transcriptome (RNA) sequencing of whole blood was performed.

Findings:

• A pathogenic deep intronic variant in the CLCN7 gene was identified.
• This variant created an unexpected, frameshifting pseudoexon, leading to complete loss of gene function.
• Functional studies confirmed normal osteoclast differentiation but impaired osteoclast function.

Implications:

• This is the first report of a pathogenic deep intronic CLCN7 variant.
• The study demonstrates RNA sequencing's utility in identifying noncoding variants causing osteopetrosis.
• Early molecular diagnosis is crucial for potentially curative treatments like hematopoietic stem cell transplantation.
• Cryptic splice variants missed by DNA sequencing highlight the value of broad transcriptome sequencing for undiagnosed pediatric diseases.