Absence of Missense Variant Detection in Inherited Dysfibrinogenemia May Result from a Poor Raw Data Analysis...

Area of Science:

• Genetics
• Molecular Biology
• Hematology

Background:

• Inherited dysfibrinogenemia is a rare bleeding disorder caused by genetic mutations in fibrinogen genes.
• Standard Sanger sequencing is typically effective for identifying causative DNA variants.
• Exceptional cases of variant identification failure necessitate further investigation.

Observation:

• Two cases of inherited dysfibrinogenemia presented with unidentified DNA variants after Sanger sequencing.
• The first case's failure was attributed to raw signal overcorrection by analysis software.
• The second case represented the first documented instance of mosaicism in a fibrinogen gene.

Findings:

• Sanger sequencing failed to detect the underlying genetic cause in two dysfibrinogenemia patients.
• Software-induced signal overcorrection masked a variant in the first patient.
• Low-level mosaicism in a fibrinogen gene was identified in the second patient using next-generation sequencing (NGS).

Implications:

• This study highlights limitations of Sanger sequencing in specific dysfibrinogenemia cases.
• It underscores the importance of considering software artifacts in genetic analysis.
• The findings emphasize NGS as a crucial tool for detecting mosaic variants in inherited bleeding disorders.