Resolution of Disease Phenotypes Resulting from Multilocus Genomic Variation

Area of Science:

• Genomics
• Clinical Diagnostics
• Human Genetics

Background:

• Whole-exome sequencing (WES) is a powerful tool for linking clinical phenotypes to genotypes.
• Understanding the frequency and characteristics of multiple molecular diagnoses is crucial for accurate genetic diagnostics.

Purpose of the Study:

• To determine the frequency and clinical characteristics of patients with multiple molecular diagnoses identified through WES.
• To assess the phenotypic similarity between co-occurring molecular diagnoses using the Human Phenotype Ontology.

Main Methods:

• Retrospective analysis of WES data from 7374 unrelated patients.
• Calculation of phenotypic similarity using Human Phenotype Ontology terms for patients with multiple diagnoses.
• Analysis of parental samples to determine the origin of variants (de novo or inherited).

Main Results:

• A molecular diagnosis was achieved in 28.2% of patients; 4.9% had multiple molecular diagnoses.
• De novo variants were common, particularly in autosomal dominant and X-linked genes.
• Phenotypic similarity was significantly lower in patients with distinct, non-overlapping mendelian disorders affecting different organ systems.

Conclusions:

• Multiple molecular diagnoses occur in 4.9% of informative WES cases.
• Structured clinical ontologies effectively quantify phenotypic overlap between distinct or overlapping mendelian disorders.
• Understanding disease overlap aids in diagnosing complex genetic conditions.