This document summarizes genetics research on Frontotemporal Dementia (FTD). It finds that 20-40% of FTD cases are familial, with several genes identified as causing different inheritance patterns of FTD. The most common gene is C9orf72, present in around 25% of cases, followed by MAPT (10-20% of familial, 0-3% of sporadic cases) and GRN (5-10% of familial, 1-5% of sporadic cases). Different genes correlate with different pathological phenotypes of tau-related, TDP-43, or FUS/FTLD-U protein aggregations. Each gene is summarized in terms of total mutations identified,

1. Genetics of Frontotemporal
Dementia
Dr.Leena Shingavi
M.B.B.S., PhD Clinical Neurosciences (2nd year)

2. Introduction:
• Frontotemporal Dementia (FTD) is the second most common
neurodegenerative dementia after Alzheimer’s Dementia.
• Of all FTD patients, 20-40-% are familial.

3. Genes identified:
• The inheritance is in the Autosomal Dominant pattern for most genes
identified.
• Atypical PSP secondary to MAPT mutation is AR and
• Susceptibility to Parkinson’s disease can be multifactorial.
• The inheritance pattern of ALS with or without FTD owing to mutation
in VCP and FUS is undetermined.

4. Inheritance pattern of individual genes:
GENE INHERITANCE PATTERN
c9orf72 AD
MAPT AD
GRN AD
CHMP2B AD
VCP AD
TARDBP AD/AR
FUS AD/AR
SIGMAR1 AD/AR
SQSTM1 AD
TREM2 AR
OPTN AD/AR
TBK1 AD
CHCHD10 AD with incomplete penetrance
PRKAR1B AD
hnRNPA2B1 Unknown
UBQLN2 X-linked Dominant
CSF1R AD
DCTN1 AD
MATR3 AD

5. Tau related TDP-43 FTLD-FUS/FTLD-U
MAPT(microtubule
associated protein tau)
TARBDP(tar DNA binding
protein,
C9ORF72(chromosome 9
open reading frame 72),
GRN (progranulin),,
VCP(valosin containing
protein)
FUS(fused in sarcoma),
CHMP2B (chromatin
modifying protein 2B).
Genotype and Pathological Phenotype correlation:

6. Prevalence of genes identified:
• The most common gene identified in FTD is c90rf72 around 25%, MAPT-10-
20% in familial and 0-3% in sporadic FTD, GRN-5-10% in familial cases and 1-
5% in sporadic FTD.
• Other genes being rare.
• VCP-1.6%
• TARDNA less than 20 cases described.
• CHMP2B, TBK1, FUS, etc. are very rare.
Prevalence of genes in FTD
C9ORF72 MAPT GRN OTHERS

7. C9orf72 (chromosome 9 open reading frame 72):
• No domains identified.
• 8 GGGGCC repeat variation mutations are present in the intronic region.
• Repeat locus being at 9p21.
• Normal repeat number – 1 to 30.
• In disease state hundreds to thousands repeats are identified in one allele
with other allele having normal repeats.
• RNA gain of function mutation is thought to be the pathogenic mechanism.

8. MAPT (Microtubule associated protein tau):
Total mutations-85.
Missense mutation:54, splicing-21, regulatory-3, small deletions-2, gross insertions-1, gross
insertions/duplications-4 and complex rearrangements-1.

9. GRN (Progranulin):
Total mutations-144.
Missense/Nonsense mutations-35, nonsense mutation;22, splicing-19, regulatory-5,
small deletions-37, small insertions-16, small indels-1, gross deletions-9. Missense mutation –
Nonsense mutation -

10. VCP (Valosin-containing protein):
Total mutations-33.
Missense mutations-33

11. CHMP2B (Chromatin modifying protein 2B):
Total mutations:17
Missense mutations:12, nonsense mutations:2, Gross
deletions:2, Splicing:1.
Nonsense mutation
Missense mutation

12. TARDBP(TAR DNA binding protein):
Total mutations:60
Missense mutations:50, splicing:3, regulatory:3, small deletions:2, small insertions:1, small indels:1.

13. FUS(Fused in Sarcoma):
Total mutations:81, missense mutations:41, nonsense mutation:3, splicing:5,
regulatory:7, small deletions:14, small insertions:5, small indels:3, gross deletions:2,
complex rearrangements:1 Nonsense mutation
Missense mutation

14. TBK1(TANK Binding kinase 1):
Total mutations:37,
missense mutation:21, nonsense mutations:5, splicing:3, small deletions:4, small insertions:2.
Nonsense mutation
Missense mutation

15. ITM2B(Integral Membrane Protein 2B):
Total mutations:2
Missense mutation:1, small insertion:1

16. PSEN1(Presenilin 1):
Total mutation:17
Missense mutation:14, gross deletions:3

17. PSEN2 (Presenilin 2):
Total mutations:2;
missense mutation:2

18. TUBA4A(Tubulin alpha 4A chain):
Total mutations:13.
Missense mutation:11, nonsense mutation:1, Splice donor site mutation:1
Missense mutation –
Nonsense mutation -

19. SQSTM1 (Sequestome 1):
Total mutation:68.
Missense mutation:54, nonsense mutation:3, splicing:4, small deletions:5, small
insertions:2.
Missense mutation –
Nonsense mutation -

20. DCTN 1 (Dynactin):
Total mutations:9.
Missense mutation:8, Splice site:1

21. OPTN (Optineurin):
Total mutations:26.
Missense mutations:15, nonsense mutations:3, splicing:2, small deletions:2, small
indels:1, gross deletions:3
Missense mutation –
Nonsense mutation -

22. MATR3 (Matrin 3):
Total mutations (missense mutation):3

23. SIGMAR1 (Sigma Non-opioid Intracellular receptor 1):
Total mutations:3,
Missense mutations:2, regulatory:5

24. CHCHD10 (Coiled coil helix-Colied coil helix
domain containing 10):
Total mutations;14
Missense mutations;12, Nonsense mutations:2
Missense mutations –
Nonsense mutations -

25. PRKAR1B (Protein kinase A type 1 beta
regulatory subunit):
Total mutation:1 (missense mutation)

26. hnRNPA2B1 (heterogenous nuclear
ribonucleoprotein A2B1):
Total mutation:1 (missense mutation)

27. UBQLN2 (Ubiquilin 2):
Total mutation:18 (missense mutation)

28. TREM2(Triggering receptor expressed on
myeloid cells 2):
Total mutations:21,
Missense mutations:14, nonsense mutation:5, splicing:1, small
deletion:1
Missense mutations –
Nonsense mutations -

29. Thank you