Germline Mutation

Germline mutation is an alteration of genetic matter which occurs after the time of conception and affects germ cells (eggs and sperm). A principal consequence of affecting germ cells is that such mutations may be passed to offspring.

Another key consideration is that a germline mutation will likely have few, if any, consequences for the individual with the mutation. Instead, the consequences accrue the offspring. Mutations of this sort are critical in understanding Alfred G. Knud-son's two-hit hypothesis of heritable cancers as well as the spontaneous appearance of phenotypes associated with dominant inheritance in otherwise normal families.

Retinoblastoma is the paradigmatic model of the role of germline mutations in cancer caused by the loss of tumor-supressor function. Retinoblastoma appears in two forms: heritable and sporadic, with heritable cancers accounting for 40 percent of the disease. In this form, a child inherits one wildtype allele and one mutant allele at the retinoblastoma locus. This first mutation is Knudson's first hit. Cells heterozygous at the retinoblastoma locus show a normal phenotype until a somatic mutation occurs at the wildtype retinoblastoma locus (Knudson's second hit). Because this mutation eliminates the only remaining DNA sequence to code for the working tumor suppressor, the resulting cell is without this tumor suppressor's capabilities and is likely to accumulate other somatic mutations at an increased rate and progress to a tumor.

In contrast, the 60 percent of sporadic cancers of this type require two somatic mutations of the retinoblastoma gene, an unlikely event in an otherwise normal cell. Because of these two different mechanisms of tumorigenesis, cancers of this type present differently in the heritable and sporadic modes. Because the underlying somatic mutation in the heritable form is much more likely, heritable cancers of this type occur simultaneously in multiple locations from multiple progenitor cells. Even if all such tumors are excised and the cancer goes into remission, relapse is likely throughout life. In contrast, sporadic cancers of this type occur singly, from a single progenitor cell and are unlikely to recur if cured.

There are two ways a dominant mutation can affect a child born to two parents who do not carry the mutation: somatic mutation early in embryogenesis giving rise to a mosaic dominated by the mutant phenotype or germline mutation in one of the parents. The former is exceedingly rare. However, for certain conditions such as osteogenesis imperfecta, certain hemophilias and Duchene's muscular dystrophy, germline mutation may increase the risk of recurrence by several orders of magnitude (to as high as 15 percent). Consideration of the role of mosaicism in atypical inheritance is now considered standard practice in genetic testing and counseling.