P-521 Importance of full clinical presentation for precise diagnosis by WES: a clinical geneticist’s viewpoint
Authors: Mykytenko D 
Published: June 2022

Study question

To what extent is the fullness and detail of the description of a patient’s clinical presentation necessary to ensure the precise diagnosis by WES?

Summary answer

A full clinical presentation and description of a patient’s phenotype are critical to reduce the incidence of false-negative results at the WES bioinformatics processing stage.

What is known already

Whole Exome Sequencing (WES) is a powerful method of genetic testing. However, genetic laboratory business models have created conditions where doctors of any specialty or patients themselves can send a biosample for testing. That being said, the lack of understanding by doctors and patients of the testing principles and the testing accessibility creates a misconception regarding the simplicity of the diagnosis and can lead to critical errors when conducting bioinformatics processing. Errors may include the derivation of an excessive number of variants without clinical significance which will make genetic counseling too difficult, can lead to false-negative results and/or misdiagnosis.

Study design, size, duration

Retrospective bioinformatics reanalysis of raw sequencing data (RAW data) for patients seeking genetic counseling to clinically interpret WES results in case of negative results (no mutations identified) (2020-2021). Group A – patients (24 cases, full clinical information collection, patient phenotyping, HPO-coding when referring to WES). Group B – patients (12) who underwent WES only with a diagnosis. Group C – patients (15) who underwent WES with clinical information, but without a description of the phenotype.

Participants/materials, setting, methods

The study included cases of negative WES results in the case of examinations of children with undifferentiated neuropsychiatric retardation aged 1 to 5 years for whom clinical interpretation of WES results was performed independently of the WES implementing laboratory. For all negative results, RAW data bioinformatics re-processing was performed in an independent laboratory. For groups B and C – after full clinical information collection, phenotype description, and HPO coding.

Main results and the role of chance

Bioinformatics re-analysis in an independent laboratory in the group with a full patient description (A) allowed to identify 2 positive cases out of 24 previously negative ones (8.3%). In group B – 5 cases out of 12 (41.7%) after full clinical information collection, phenotype description, and HPO-coding. In group C, with full phenotype description and HPO coding, – 3 cases out of 15 (20%). Overall chi-sq (2;N=51)=5.64 p = 0.059 Group A vs B: chi-sq (1;N=36)=5.67 p = 0.017 (significant at p ≤ 0.05) Group A vs C: chi-sq (1;N=39)=1.12 p = 0.28 (not significant at p ≤ 0.05) Group B vs C: chi-sq (1;N=27)=1.05 p = 0.22 (not significant at p ≤ 0.05)

Limitations, reasons for caution

The study results and the evaluation of statistical significance criteria are limited to a small sample with negative WES results, and also apply only to children with undifferentiated neuropsychiatric retardation aged 1 to 5 years.

Wider implications of the findings

The study results may serve as a basis for modifying the requirements of genetic laboratories for the description of a clinical case during referral for diagnosis by WES. Such modifications will allow geneticists to find a precise diagnosis and provide reproductive family planning and PGT procedures

Trial registration number

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