Clinical Trial Summary
Intellectual deficiency (ID) is a veritable public health issue because it affects 1 to 3% of
the population at large. Currently, in France, the diagnosis is based on clinical expertise,
the use of DNA microarray analysis, screening for fragile-X syndrome and, if necessary, a
study of target genes depending on the clinical data. Although clinical expertise is not
enough to target one gene in particular, these different tools currently lead to diagnosis in
only 20% of patients on average (higher percentage in cases of syndromic intellectual
deficiency), sometimes after numerous expensive biological examinations.
Thanks to high-throughput sequencing (HTS), medical genetics is experiencing a major
technological upheaval, originating from the development of sequencing panels of target
genes, such as, for example, the DI459 panel, composed of 459 genes implicated in or likely
to be implicated in ID, developed by the team in Strasbourg and whole-exome sequencing (WES).
The deployment of HTS in diagnosis has occurred at different speeds depending on the country,
some of which have been using it in routine diagnosis for several years. The type of strategy
to adopt in development anomalies is still a matter of debate in France, in the absence of
results from cost-effectiveness analyses; this absence has hampered the implementation of
these technologies.
In the diagnosis of ID, the DI459 panel has a diagnostic yield of 25%. Data in the literature
also show a high efficacy of WES in patients with ID: approximately 32% of genetic diagnoses
(progressively increasing thanks to possible reanalysis as knowledge of genomics advances)
and 10% of additional diagnoses through the identification of chromosomal
micro-rearrangements, making an expected total of 42% of diagnoses. WES could thus replace
array-CGH. The cost is higher than that for the DI44 and DI459 panels, but it means that
examinations don't have to be repeated sequentially over time if the investigations are
negative.
The question of medico-economic value is thus central so as to determine which strategy is
the most effective. A few medico-economic studies, comparing classical investigations with
WES, have already been carried out concerning the use of HTS for diagnostic purposes, but
none have concerned ID, or compared panel sequencing with WES. In this context, a
medico-economic study is essential in France, because ultimately the choice of the most
appropriate HTS strategy in the diagnosis of ID will have major repercussions not only
clinical and economic, but also for society at large, on the one hand because of the benefits
1) for the management and prognosis of patients, and 2) for families as they will have
improved access to genetic counselling. It is important to note that the Genetic community
has never experienced such a huge technological innovation, which will lead to a massive
increase in diagnostic yield, thus justifying the interest that the community must give to
this innovation.
