There is a deep need to navigate within our genomic data to find, understand and pave
the way for disease-specific treatments, as the clinical diagnostic journey provides
only limited guidance. The human genome is enclosed in every nucleated cell, and yet
at the single-cell resolution many unanswered questions remain, as most of the sequencing
techniques use a bulk approach. Therefore, heterogeneity, mosaicism and many complex
structural variants remain partially uncovered. As a conceptual approach, nanopore-based
sequencing holds the promise of being a single-molecule-based, long-read and high-resolution
technique, with the ability of uncovering the nucleic acid sequence and methylation
almost in real time. A key limiting factor of current clinical genetics is the deciphering
of key disease-causing genomic sequences. As the technological revolution is expanding
regarding genetic data, the interpretation of genotype–phenotype correlations should
be made with fine caution, as more and more evidence points toward the presence of
more than one pathogenic variant acting together as a result of intergenic interplay
in the background of a certain phenotype observed in a patient. This is in conjunction
with the observation that many inheritable disorders manifest in a phenotypic spectrum,
even in an intra-familial way. In the present review, we summarized the relevant data
on nanopore sequencing regarding clinical genomics as well as highlighted the importance
and content of pre-test and post-test genetic counselling, yielding a complex approach
to phenotype-driven molecular diagnosis. This should significantly lower the time-to-right
diagnosis as well lower the time required to complete a currently incomplete genotype–phenotype
axis, which will boost the chance of establishing a new actionable diagnosis followed
by therapeutical approach.
