FTD Genetics and You:
Genes are the segments of DNA that contain “recipes” for making the proteins that carry out the functions needed to keep cells alive. Variants are changes in the DNA sequence of a gene. Like typos in a cookbook recipe, variants lead to changes in the instructions for making the protein encoded by the gene.
In some cases, FTD is caused by harmful genetic variants that affect proteins essential to the normal functioning and survival of brain cells. Researchers have identified three genes that account for the majority of inherited FTD cases, as well as a number of additional genes that, while rare, are also believed to cause FTD.
Common Genetic Variants Leading to FTD
C9orf72 — Most common gene associated with hereditary FTD and ALS
The genetic change in the C9orf72 gene is typically a repeat of a DNA segment (GGGGCC). This DNA segment is typically repeated from 2 to about 24 times for each of us. For people with FTD or ALS, however, this GGGGCC segment is repeated more than 60 times. The abnormally expanded GGGGCC segment disrupts the C9orf72 gene, leading to a cascade of events which result in abnormal accumulation of TDP-43 protein.
Repeat sizes between 24 and 60 are considered “intermediate,” but it is not clear at this time whether, or how frequently, “intermediate” expansions cause FTD or ALS.
The GRN gene provides instructions for making a protein called progranulin. Variants in the GRN gene lead to reduced levels of progranulin, a protein that is involved in cell survival and regulating inflammation.
People with GRN genetic variants have abnormal accumulation of a protein called TDP-43 in the brain, although the relationship between GRN variants, decreased levels of progranulin, and abnormal accumulation of TDP-43 protein is not fully understood today.
MAPT (Microtubule-associated protein tau)
The MAPT gene provides instructions for making a protein called tau. Variants in the gene result in a tau protein accumulating abnormally in the brain. Tau typically plays a role in the assembly and stabilization of nerve cells in the brain cells.
Some types of FTD are associated with variants in specific genes. For example, people diagnosed with FTD-ALS are more likely to have a genetic variant in C9orf72, compared to other genetic changes. Other types of FTD, like bvFTD, do not appear to have the same gene/disease association. Genetic variants in all three major genes associated with FTD have been seen in people with bvFTD.
Variants in other genes have also been described, but are much rarer than the three mentioned above. These other FTD-associated genetic variants include VCP, CHMP2B, TARDBP, FUS, SQSTM1, CHCHD10, TBK1, OPTN, CCNF, and TIA1 (Greaves & Rohrer, 2019).