A unique case of neurodevelopmental disorders and epilepsy linked to WDR45 variant inheritance and maternal mosaicism

Area of Science:

• Genetics
• Developmental Biology
• Neurology

Background:

• WDR45 gene mutations are associated with Coffin-Siris syndrome, a rare genetic disorder.
• Mosaicism, where a person has cells with different genetic makeups, can complicate genetic diagnosis.
• Understanding inheritance patterns of rare genetic variants is crucial for genetic counseling.

Observation:

• A male infant presented with psychomotor developmental delay, epilepsy, and abnormal liver function.
• High-throughput sequencing identified a likely pathogenic hemizygous WDR45 variant (c.867_869dupGTA, p.Y290*) in the proband.
• The same WDR45 variant was detected in the amniotic fluid of a subsequent fetus and in low-level mosaic form (4.06% mutation load) in the asymptomatic mother.

Findings:

• The study identified a de novo WDR45 variant in the proband, inherited from a mosaic mother.
• Deep sequencing confirmed the presence of the WDR45 variant in the mother's cells, indicating germline mosaicism.
• The findings demonstrate that asymptomatic carriers with low-level mosaicism can transmit pathogenic variants.

Implications:

• This case highlights the importance of considering parental mosaicism in genetic diagnoses, even with asymptomatic parents.
• It underscores the need for advanced sequencing techniques to detect low-level mosaic variants.
• Accurate identification of mosaic variants is critical for prenatal diagnosis and family genetic counseling.