Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease

Martin A. Kohli, Holly N Cukier, Kara L. Hamilton-Nelson, Sophie Rolati, Brian W. Kunkle, Patrice L. Whitehead, Stephan L Zuchner, Lindsay A. Farrer, Eden R Martin, Gary W Beecham, Jonathan L. Haines, Jeffery M Vance, Michael Cuccaro, John Gilbert, Gerard D. Schellenberg, Regina M. Carney, Margaret A Pericak-Vance

Research output: Contribution to journalArticle

19 Scopus citations


Objective: The genetic risk architecture of Alzheimer disease (AD) is complex with single pathogenic mutations leading to early-onset AD, while both rare and common genetic susceptibility variants contribute to the more widespread late-onset AD (LOAD); we sought to discover novel genes contributing to LOAD risk. Methods: Whole-exome sequencing and genome-wide genotyping were performed on 11 affected individuals in an extended family with an apparent autosomal dominant pattern of LOAD. Variants of interest were then evaluated in a large cohort of LOAD cases and aged controls. Results: We detected a single rare, nonsynonymous variant shared in all 11 LOAD individuals, a missense change in the tetratricopeptide repeat domain 3 (TTC3) gene. The missense variant, rs377155188 (p.S1038C), is predicted to be damaging. Affecteds-only multipoint linkage analysis demonstrated that this region of TTC3 has a LOD score of 2.66 in this family. Conclusion: The TTC3 p.S1038C substitution may represent a segregating, rare LOAD risk variant. Previous studies have shown that TTC3 expression is consistently reduced in LOAD patients and negatively correlated with AD neuropathology and that TTC3 is a regulator of Akt signaling, a key pathway disrupted in LOAD. This study demonstrates how utilizing whole-exome sequencing in a large, multigenerational family with a high incidence of LOAD could reveal a novel candidate gene.

Original languageEnglish (US)
Article numbere41
JournalNeurology: Genetics
Issue number1
StatePublished - Feb 1 2016


ASJC Scopus subject areas

  • Clinical Neurology
  • Genetics(clinical)

Cite this

Kohli, M. A., Cukier, H. N., Hamilton-Nelson, K. L., Rolati, S., Kunkle, B. W., Whitehead, P. L., Zuchner, S. L., Farrer, L. A., Martin, E. R., Beecham, G. W., Haines, J. L., Vance, J. M., Cuccaro, M., Gilbert, J., Schellenberg, G. D., Carney, R. M., & Pericak-Vance, M. A. (2016). Segregation of a rare TTC3 variant in an extended family with late-onset Alzheimer disease. Neurology: Genetics, 2(1), [e41].