Medical genetics is experiencing an exciting and disruptive technological revolution.
Next-generation sequencing (NGS) technologies are enabling simultaneous sequencing
of all relevant disease genes, the exome or even the entire genome of patients seeking
a molecular diagnosis. This can be performed on small sample volumes and even single
cells with near-perfect accuracy, in days rather than months, and at more and more
affordable pricing, allowing widespread implementation in the clinic 1]. This is an important moment in the history of medical genetics, because for the
first time we can study a person’s entire genome in our quest to find the genetic
causes underlying disease and/or those potentially having an impact on clinical response
to treatment.
Genome sequencing, although still imperfect, will enable the detection of all types
of genomic variation in a single experiment, including point mutations or single nucleotide
variants, insertion-deletions, repeat expansions and larger structural variations
such as copy number variants and copy-number-neutral inversions and translocations.
Although genome sequencing is currently more expensive than targeted disease gene
or exome sequencing as calculated on a per test basis, this may not be the case when
calculated on a per patient basis. Pilot studies have already demonstrated that genome
sequencing can reveal causative mutations or structural variations missed by other
genetic tests, including Sanger sequencing, exome sequencing and genomic microarrays
2], 3]. Regardless of which NGS approach is used, it is evident that variant identification
is becoming more and more readily attainable, whereas variant interpretation in each
individual patient remains a major challenge 4], 5]. This has considerable consequences for medical genetics laboratories, where there
will be less need for expertise in laboratory data generation and increased demand
and necessity for expert data analysis and interpretation.
Single-test or comprehensive genetic testing, such as that provided by genome sequencing,
has many important advantages in the clinic. It allows automated laboratory procedures
and standardization of variant calling and reporting. No longer is a subjective clinical
decision required to determine which genetic test to perform and in which patient.
Instead, implementation of a single genetic test is sufficient. It is conceivable
that best practice will evolve to a point at which genome sequencing will be performed
before a patient even visits a clinician. This may enable the clinician to capitalize
on the genomic information immediately and use it to form a diagnosis.
Comprehensive genomic sequencing requires a different skill set for clinical geneticists
and other medical professionals using genetic data. The genomic data from patients,
collected in a standardized format all over the globe, will be enormously valuable
to improve our understanding of variant pathogenicity and disease susceptibility.
Data sharing on a global scale is therefore essential to improved understanding of
genotype–phenotype correlations 6]. Global data sharing is not just a lofty goal but rather a requirement for understanding
human biology and deviations from homeostasis or health; it transcends geographic,
political and religious boundaries that can sometimes divide the human race. These
genomic data are, however, useful only if combined with phenotypic information collected
in a standardized manner as well. It is remarkable to think that genome sequencing
itself may soon turn out to be the easy part of the equation. Standardized phenotyping
all over the world is likely to be a major challenge required for maximizing the medical
knowledge acquisition from personal genomic variant information. This requires clinicians
to adapt their clinical practice and potentially adopt and incorporate novel phenotyping
tools.
Clearly, there are ethical and legal issues related to medical genome sequencing.
These are mostly related to ownership and privacy of personal data and the risk of
detecting clinically relevant genomic variants unrelated to the original clinical
conundrum and concern for which the patient visited the clinician 7]. Patients need to be protected from misuse of their genomic data and need to be adequately
counseled so that they can understand the information contained in their genome and
the current limitations of medical knowledge. In this regard, an obligation of the
community of geneticists and genomicists will be to educate the physicians, patients
and public about DNA, the genetic code, genomics and its role in human biology, health
and disease susceptibility. The growth of genome sequencing capacity is impressive
by any measure, with commercial platforms now being able to sequence 10,000–50,000
genomes per year. This has spurred a range of national programs, such as the 100,000
Genomes Project in the United Kingdom (http://genomicsengland.co.uk), FarGen (http://www.fargen.fo/en) in the Faroe Islands, and the precision medicine initiatives in the USA (http://www.nih.gov/precisionmedicine/) and Saudi Arabia (http://shgp.kacst.edu.sa/site/). At the same time, individual medical genetics laboratories around the globe are
learning to interpret individual variation obtained from targeted disease gene and
exome sequencing in their clinics on a daily basis.