Rare Disease Day is coming up February 29 (a rare day for rare diseases). In honor of the upcoming event, I'll be posting blogs all month, related to the rare diseases and to rare disease funding.
A significant but unquantified portion of genetic diseases is non-inherited; occurring from de novo (new) mutations in the the germ cells of the affected individuals. In humans, point mutations (i.e., mutations that occur in a single nucleotide base within the genome) occur with a frequency of about 1 to 3 x 10-8 per base (1), (2). There are many types of mutational alterations other than point mutations (e.g., mutations in microsatellites) (3). Our knowledge of the likelihood of other types of mutation most of these alternate types of mutation is limited. In many cases de novo mutations cause lethal genetic diseases that occur in children, through the action of a dominant gene (i.e., one gene copy that produces the disease). Such diseases are seldom inherited because they cannot be conserved in the population; those with the gene die early in life, without passing the gene to progeny. Sometimes, non-inheritance accounts for some proportion of cases that would otherwise occur as dominant gene disorders. Neurofibromatosis is an example of a disease that occurs through autosomal dominant inheritance in about half of the cases. The other half of occurrences are de novo mutations incurring in the affected individual. In general, de novo mutations are often suspected as the cause of diseases that occur in early childhood for which no other cause (e.g., no evidence of familial or parental inheritance, infectious etiology, or environmental influences) can be determined (e.g., autism) (4). See De novo mutation.
- Jules Berman (copyrighted material)
key words: rare disease, orphan drugs, orphan diseases, zebra diseases, rare disease day, jules j berman
 Nachman MW, Crowell SL. Estimate of the mutation rate per nucleotide in humans. Genetics 156, 297-304, 2000.
 Roach JC, Glusman G, Smit AF, Huff CD, Hubley R, Shannon PT, et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Science 328:636-639, 2010.
 Whittaker JC, Harbord RM, Boxall N, Mackay I, Dawson G, Sibly RM. Likelihood-based estimation of microsatellite mutation rates. Genetics 164:781-787, 2003.
 Veltman JA, Brunner HG. De novo mutations in human genetic disease. Nat Rev Genet 13:565-575, 2012.