Identification of a Non-Coding Causative Variant Underlying Warsaw Breakage Syndrome Using Long-Read Based Genomic...

Area of Science:

• Genomics
• Rare Genetic Diseases
• Molecular Biology

Background:

• Exome and genome sequencing diagnose 30%-50% of rare genetic diseases.
• Interrogating non-coding regions with multi-modal technologies can improve diagnostic yield.
• A family presented with sensorineural hearing loss, microcephaly, intellectual impairment, and growth restriction.

Purpose of the Study:

• To identify the genetic cause of rare diseases in siblings using advanced sequencing techniques.
• To demonstrate the utility of multi-modal genome-wide approaches for diagnosing rare genetic conditions.

Main Methods:

• Long-read whole genome and cDNA-based transcriptome sequencing on the Oxford Nanopore platform.
• Analysis of non-coding genomic regions, including the 5' UTR and promoter.
• Integration of multi-modal data for variant prioritization.

Main Results:

• A homozygous 1.6 kb deletion in the 5' UTR and promoter region of the DDX11 gene was identified.
• The deletion encompassed a regulatory CpG island, leading to loss of DDX11 mRNA and protein expression.
• The characteristic "railroad chromosome" phenotype was observed, consistent with Warsaw breakage syndrome.

Conclusions:

• Expanding genomic variant searches beyond protein-coding regions is crucial for diagnosing rare diseases.
• Multi-modal data integration enhances variant classification and diagnostic capabilities.
• This genome-wide approach offers hope for patients with undiagnosed genetic conditions.