Exome sequencing redefining phenotypes

Posted by & filed under Exome sequencing, Part 06: DIAGNOSTIC APPROACHES, Part 28: NEUROGENETICS, Part 30: MULTISYSTEM INBORN ERRORS OF DEVELOPMENT.

One would intuitively expect that Whole-exome sequencing (WES) will help broaden the phenotypic spectrum of known syndromes since in the past only patients closely matching the described phenotype of a documented genetic syndrome would be tested for the respective diagnosis.

Some recent examples illustrating the direction the field is moving include the publications of Dr. Boycott’s group in Clinical Genetics: Dymetry et al. (2014) describe four patients with an atypical presentation of the genetic diagnoses which were found to explain their epilepsy after WES. Similarly, Nikkel et al. (2014) describe the atypical phenotype of a family with Hunter syndrome.

These are exciting findings and demonstrate how useful WES can be at a clinical level. However, as the field advances, one also needs to keep in mind that the expansion of the phenotypes will yield increasingly more cases where concluding whether a mutation in a gene associated with a specific syndrome is the explanation for the patient’s phenotype is more difficult. Multiple findings in different genes may be perceived to possibly explain the phenotype independently.  This is already true when using Next Gen sequencing panels.

Making use of different levels of phenotypic information (e.g. metabolomics, transcriptomics, proteomics) in clinic and a network-based approach may prove helpful to this end.


Whole-exome sequencing expands the phenotype of Hunter syndrome. Nikkel et al. Clin Genet. 2014 Aug;86(2):172-6. PMID: 23844659

Whole-exome sequencing broadens the phenotypic spectrum of rare pediatric epilepsy: Aretrospective study. Dyment DA, et al. Clin Genet. 2014 Jul 21. doi: 10.1111/cge.12464. [Epub ahead of print]

Posted by Yannis Trakadis, MD

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