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Phenotypic refinement critical in exome interpretation

A recent study published in Genetics in Medicine explored the importance of refining phenotypic information for more effective exome data interpretation.

Identifying disease-causing variants

The identification of disease-causing variants from next-generation sequencing data remains an ongoing challenge. The current ACMG/AMP variant classification largely focuses on the molecular and functional features of variants. However, there are only a few criteria that consider phenotype.

The clinical data given to genomic laboratories is often scarce. It is important to have in-depth phenotypic data to completely understand whether clinical presentation is compatible with molecular findings. The requirements for the minimum set of information that should be communicated to these laboratories has not yet been defined.

Phenotypic refinement

In this study, researchers described in what scenarios phenotypic refinement may be important in the interpretation of exome data. 209 out of 614 exomes had a diagnosis and were therefore included in the study. In addition, researchers obtained phenotypic information from genetic counselling letters and images. They also contacted referring clinicians for clarification if there were any discrepancies. In 16/209 cases, there were discrepancies between candidate variant segregation and expected disease status. The team felt that these cases necessitated refinement of phenotypic information. These were due to the following:

  • Disease-causing variants did not co-segregate with reported phenotype.
  • Different disorders with overlapping symptoms in the same family were identified.
  • Similar features found in proband and family members, but molecular cause only identified in proband.
  • Previously unrecognised maternal condition was identified as causative of child’s phenotype.

Phenotypic clarification in 12/16 cases resulted in a change in a family member affected-versus-unaffected status and in 1 case, variant classification was changed (variant of uncertain significance to likely pathogenic).

 The study includes examples where a refinement of phenotypic information has resulted in a change of disease status assignment and variant reclassification. This emphasises the importance of obtaining phenotypic information and communicating this with the variant interpretation team to ensure accurate exome data interpretation.

Image credit: People vector created by pikisuperstar –

More on these topics

Exome / Phenotype / Variant Classification