A mutation can hide another one: Think Structural Variants!

Area of Science:

• Genetics
• Genomic Medicine
• Bioinformatics

Background:

• Next Generation Sequencing (NGS) is crucial for diagnosing genetic diseases.
• NGS commonly detects Single Nucleotide Variants (SNVs) and small indels.
• Structural Variants (SVs) like large deletions are frequently underdiagnosed due to limited user-friendly detection tools.

Purpose of the Study:

• To highlight the underdiagnosis of Structural Variants (SVs) in inherited genetic diseases.
• To present the successful diagnosis of two brothers with demyelinating neuropathy.
• To introduce CovCopCan software for identifying hidden SVs in NGS data.

Main Methods:

• Analysis of Next Generation Sequencing (NGS) data from two patients with neuropathy.
• Initial detection of a presumed homozygous c.5744_5745delAT mutation in the SACS gene.
• Utilized CovCopCan software to re-analyze NGS data and identify Structural Variants (SVs).

Main Results:

• Patients were initially misdiagnosed with a homozygous SACS mutation.
• CovCopCan revealed patients were heterozygous for the SNV and carried a large deletion in the other SACS allele.
• The hidden deletion in the SACS gene was identified as the cause of the neuropathy.

Conclusions:

• Structural Variants (SVs), including large deletions, are often missed by standard NGS analysis.
• User-friendly software like CovCopCan is essential for comprehensive NGS data screening.
• Systematic use of SV detection tools can improve the diagnostic rate for inherited genetic diseases.