Filled symbols are affected persons. They have a mutation in the so-called TRPV4 gene. Symbols with plus sign represent

unaffected carriers of the same mutation. Symbols with minus sign are persons without this mutation. As only three out of the six persons with the mutation are affected, penetrance in this pedigree is 50% (redrawn and slightly modified from Rapamycin supplier Berciano et al. 2011) Another reason why it may be difficult to deduce the pattern of inheritance directly from its occurrence in a family is the phenomenon of variable expressivity. By this we mean that a given genotype may lead to different clinical pictures in different persons. One may then assume that there are several different disorders in the family, while in fact the disorders in the family members have the same underlying genetic cause. Figure 4 shows a recently reported example of variable expressivity. Fig. 4 Pedigree of a family with different manifestations of the presence of a mutation in the

FGFR1 gene (symbols with plus sign) in three family members (redrawn and slightly modified from Au et al. 2011) When two parents are carriers of an autosomal recessive disease, each child has a 25% chance of developing that particular disease, but this also means a 75% chance of not developing the disease. If the parents have two children, there is a 56% chance that none XAV-939 concentration of them has the disease. With three children there is still a 42% chance that all will be free of the disease and so on. The chance that at least two children will

be affected, thereby indicating the familial nature of the disease, is only 6% in a two-child family, 16% in a three-child family, 26% in a four-child family and so on. With smaller family sizes, the probability that an autosomal recessive disorder within a family is recognized as familial is therefore rather limited. To a lesser extent, the same restriction applies to a patient who is the first one with an autosomal dominant disorder in the family, when this person has only one child or just a few children. There are several possible reasons why a person with an autosomal dominant disease may be Ixazomib in vitro the first to show this disease in the family. The disorder may be due to a new mutation, but it may also be that one of the parents already carries the mutation, either in all his or her cells, or as a mosaic. The reason for not showing the disease if a parent carries the mutation in all cells can be a matter of incomplete penetrance or due to variable expressivity. In some disorders, whether or not a mutation is expressed, can depend on the sex of the parent who transmitted the mutation (so-called imprinting). There are also dominant and other diseases in which penetrance and expression increase from generation to generation (so-called anticipation). In this case a seemingly harmless mutation (called a premutation) develops into a full mutation by passage to the following generation.