When phenotype does not match genotype: importance of “real-time” refining of phenotypic information for exome data interpretation

Purpose: Clinical data provided to genetic testing laboratories are frequently scarce. Our purpose was to evaluate clinical scenarios where phenotypic refinement in proband’s family members might impact exome data interpretation. Methods: Of 614 exomes, 209 were diagnostic and included in this study. Phenotypic information was gathered by the variant interpretation team from genetic counseling letters and images. If a discrepancy between reported clinical findings and presumably disease-causing variant segregation was observed, referring clinicians were contacted for phenotypic clarification. Results: In 16/209 (7.7%) cases, phenotypic refinement was important due to (1) lack of cosegregation of disease-causing variant with the reported phenotype; (2) identification of different disorders with overlapping symptoms in the same family; (3) similar features in proband and family members, but molecular cause identified in proband only; and (4) previously unrecognized maternal condition causative of child’s phenotype. As a result of phenotypic clarification, in 12/16 (75%) cases definition of affected versus unaffected status in one of the family members has changed, and in one case variant classification has changed. Conclusion: Detailed description of phenotypes in family members including differences in clinical presentations, even if subtle, are important in exome interpretation and should be communicated to the variant interpretation team.