Mosaic mutations in early-onset genetic diseases

Area of Science:

• Medical Genetics
• Genomic Medicine
• Molecular Biology

Background:

• Standard genetic testing for severe early-onset diseases focuses on de novo mutations.
• This approach often fails to detect post-zygotic mosaic mutations present in parental cells.
• Mosaic mutations, present in a subset of parental cells, can be transmitted to offspring causing disease.

Purpose of the Study:

• To develop and apply a mosaic transmission screen to identify parental mosaic mutations.
• To assess the frequency of parental mosaic transmissions in severe early-onset genetic disease cohorts.
• To evaluate the diagnostic utility of detecting mosaic mutations alongside de novo mutations.

Main Methods:

• A mosaic transmission screen was designed to detect variants with ~50% allele ratio in probands and <50% in parents.
• The screen was applied to two cohorts: 9 cases of sudden unexplained death in childhood (SUDC) and 338 cases of epileptic encephalopathy.
• Family-based genetic data from trios (proband and parents) were analyzed.

Main Results:

• Six parental mosaic transmissions were identified across both cohorts.
• The identified transmission rate of ~0.02 per trio is significantly lower than that of de novo mutations.
• Two likely disease-causing mosaic mutations were found: an SCN1A mutation in SUDC/Dravet syndrome and an SLC6A1 mutation in epileptic encephalopathy.

Conclusions:

• Explicit screening for parental mosaic mutations is a crucial complement to de novo mutation screening.
• This approach enhances the detection of genetic causes for severe early-onset diseases.
• Identifying mosaic mutations improves diagnostic yield in pediatric genetic disorders.