Grandparental genotyping enhances exome variant interpretation.

Area of Science:

• Genetics
• Molecular Biology
• Genomic Medicine

Background:

• Trio exome sequencing enhances molecular diagnosis of monogenic disorders by identifying de novo variants.
• Unrecognized heterozygous variants from unaffected parents pose interpretation challenges, potentially due to parental mosaicism, incomplete penetrance, imprinting, or skewed X-inactivation.

Observation:

• Three probands with pathogenic/likely pathogenic variants identified via exome sequencing initially appeared inherited from unaffected parents.
• Segregation analysis in the grandparent generation confirmed these variants were de novo in each proband.
• One proband exhibited skewed X-inactivation, adding complexity to variant inheritance patterns.

Findings:

• Pathogenic variants in NOTCH1, PHF6, and SOX10 were identified.
• Grandparental segregation studies are crucial for accurate variant origin determination.
• Objective genotype data can supersede subjective parental reports in exome data interpretation.

Implications:

• Highlights the necessity of thorough segregation studies, extending beyond parents to grandparents, for precise genetic diagnosis.
• Emphasizes caution in interpreting exome sequencing data, particularly when variants appear inherited from unaffected parents.
• Demonstrates how expanded genetic analysis refines exome interpretation strategies and improves diagnostic yield in rare disease investigations.