Application of Exome Sequencing to Mendelian Disorders and the Emergence of Personalised Medicine


Since the introduction of next‐generation sequencing, the field of genomic medicine has expanded rapidly. Whole‐exome sequencing (WES) can sequence thousands of functional genes at a time and has become the tool of choice for the discovery of causative genetic variants, especially for Mendelian diseases. This approach also expands the knowledge of novel mutations of established genes linked to a particular disease, and helps to uncover the complex interplay between modifier variants that contribute to a disease phenotype. For these reasons, WES can perform diagnoses that would be difficult to accomplish with traditional methods, particularly for diseases that exhibit a broad genetic or phenotypic heterogeneity. Together, these trends already have begun to influence the quality of patient care and appear to fulfil the promise of personal medicine. The article summarises recent literature that highlights these trends, and discusses the limitations and ethical considerations surrounding this new technology.

Key Concepts:

  • Next‐generation sequencing is driving the emergence of personalised medicine.

  • Superiority of WES as a diagnostic tool over traditional genetic methods is apparent, especially for diseases that are genetically and phenotypically heterogenous.

  • WES utility is a rapidly expanding field of genetic aetiology.

  • The underlying genetic complexity of monogenic diseases might have been underappreciated.

  • The clinical manifestation of monogenic diseases is driven by a complex interplay of a multitude of genetic modifiers.

  • The incidentalome remains an important ethical issue, but important steps forward have been taken with the work of Dr. Berg and collaborators commencing in 2011.

  • The rapidly expanding field of genomics faces important technical limitations: storage space and analysis capability.

  • Important ethical questions need to be addressed with regard to the use of NGS technology; this includes rights to data access and issues regarding follow‐up data reanalysis.

Keywords: whole‐exome sequencing; personalised medicine; next‐generation sequencing; Mendelian disorders; monogenic diseases; genomic medicine; genetic heterogeneity; phenotypic heterogeneity; pleiotropic effect; epistatic effect

Figure 1.

Technological advances in NGS platforms can result in improved personalised medicine treatment. Increased use of WGS, and especially WES, as the discovery tool of Mendelian disorders aetiology also allow applicability of such technology for improved clinical diagnosis. Together these trends aid the development of novel therapies on an individual basis.



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Raszek, Mikolaj M(Sep 2013) Application of Exome Sequencing to Mendelian Disorders and the Emergence of Personalised Medicine. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0024617]