Rare and Complex Diseases

A rare disease is defined in the European Union as one that affects fewer than 1 in 2,000 people (1). The road to diagnosis, often termed the “diagnostic odyssey” can last for more than 5 years (2). A total of 80% of rare diseases have a genetic component (3) so the utilisation of Next-Generation Sequencing (NGS) technology can provide information on the underlying genetic etiology, resulting in a faster diagnosis. Uncovering the underlying causes reveals precision medicine treatment options for patients and can be of huge benefit for care standards and symptom management.

Complex diseases are multifactorial and have both genetic and environmental components. The genetic background of these diseases is often polygenic and does not follow a Mendelian pattern of inheritance. Many of the mutations responsible are in complex non-coding regions of the genome and recent developments in NGS technologies have made these regions more accessible for analysis and are accelerating complex disease research.

1.Ferreira CR. The burden of rare diseases. Am J Med Genet A. 2019 Jun;179(6):885-892. doi: 10.1002/ajmg.a.61124. Epub 2019 Mar 18. PMID: 30883013.

2.Global Commission to End the Diagnostic Odyssey for Children with a Rare Disease, 2019 https://www.globalrarediseasecommission.com/AboutUs

3.Smedley, D. et al. 100,000 Genomes Pilot on Rare-Disease Diagnosis in Health Care – Preliminary Report. N. Engl. J. Med. 385, 1868–1880 (2021)

Genomics Application in Rare and Complex Diseases

The high throughput nature of whole genome and whole exome sequencing allows for the identification of rare and common genetic variants associated with specific diseases.
RNA sequencing can be used for differential expression analysis in response to certain therapeutics to assess their suitability for treatment of the disease in question. It can also illuminate on the functional consequence of variants of uncertain significance and help in prioritising variants of interest.
Epigenetic analysis is important in complex disease research given the common occurrence of variants in non-coding regions. Analysis of methylation and histone modifications provides insight into mechanisms that regulate gene activity.