Rare genetic disorders

this is cribbed from my FB page, but liked it enough that I wanted somewhere more permanent for it. The topic is the genetic analysis of rare single-gene disorders, what are some of the rationales justifying that work.

Our genome has something like 20,000 genes and we need to know what the consequences are of mutations in all of them. In some cases they will be of very general significance, such as mutations causing breast cancer or diabetes or osteoporosis; in such cases even if the genetic disease is rare the genetic pathways identified may provide new drug targets for a much larger number of people who have the same disease due to non-genetic defects in that pathway.

Moreover, even though each of these single gene disorders is individually rare, in aggregate there are thousands of them and together they comprise a significant fraction of pediatric hospital patients. Since each disorder is different, the only way to diagnose and determine optimal patient management is to understand the molecular bases of all of them - so far the human genetics community has characterized about 2500 rare genetic disorders (I personally have been involved in discovering 15 of these). That is still fewer than 20% of all potential single-gene conditions. These include very well known things like Huntington disease, cystic fibrosis, and some forms of breast and colorectal cancers, but also tons of relatively unknown (to the public) things like Marfan syndrome (maybe Lincoln had it), neurofibromatosis (elephant man), achondroplasia (many forms of dwarfism), and metabolic disorders including one that all children born in the modern world are tested for (by enzyme activity, not by DNA test) phenylketonuria. In addition, by studying the genomes of patients with rare disorders, we are learning a lot simply about genetic variation, which is essential for when we move on to trying to understand the genetic component of more complex diseases which have multiple genetic and environmental factors. At the moment we are not really smart enough to tackle that problem (although many scientists are trying), we have to take baby steps. On a purely logistic note, these kinds of discoveries (for rare genetic disorders) cost on the order of thousands of dollars each, sounds like a lot but compared to hundreds of millions that are spent on diabetes, obesity, cancer it's a superb return on investment to the taxpayer