"Mendelian" or "orphan" hereditary diseases account for approximately 8,000 different clinical presentations.

While rare, they affect millions of people and their families (Orphanet J Rare Dis 2019; 14:153).

A large number of these diseases are of molecular origin, which can be diagnosed using genomic technologies, thus improving the management of these patients.

Currently we know the molecular basis responsible for 6,685 traits (disease or hereditary predisposition) and 4,289 gene mutations associated with a disease (statistic as at 1 July 2020; https://omim.org/statistics/geneMap).

The technologies making it possible to determine their molecular cause are karyotyping (very rarely in the case of a specific suspected condition), comparative genomic hybridisation (CGH), clinical exome sequencing and, more recently, whole genome sequencing (Nature 583, 96-102 (2020)).

In practice, in-depth evaluation of the clinical presentation by a specialist in genetic medicine, together with the family tree of the family concerned, going back three or four generations, will make it possible to formulate a hypothesis as to the probable causal link between the disease and the candidate gene(s) under consideration. An application for treatment is then submitted to the insurance company's medical advisers (this application must be drawn up by a Swiss Medical Association genetics specialist when 10 genes or more will be analysed).

The prescription will be made on the basis of findings and the hypothesis. If only one or a small group of genes is involved, a targeted analysis will be performed. If a greater number is involved, a gene panel will be selected. Finally, if no specific hypothesis is possible, as many disease-causing genes as possible will be analysed (e.g. the 5,430 candidate genes associated with CDG [closest disease-causing genes] diseases) (Front Immunol 2018; 9:1340).

In the near future, it will also be possible to routinely analyse the whole genome, if the clinical exome does not give convincing results. A very recent study (Nature 583, 96-102 (2020)) provides proof of principle for 13,037 participants, of whom 9,802 had an orphan disease. Of 7,065 patients suffering from clearly-characterised orphan diseases, 1,138 received a definitive genetic diagnosis

Genesupport - Adult genetical and hereditary diseases