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. Züchner, Lindsay A. Farrer, Eden R. Martin, Gary W. Beecham, Jonathan L. Haines, Jeffery M. Vance, Michael L. Cuccaro, John R. Gilbert, Gerard D. Schellenberg, Regina M. Carney, Margaret A. Pericak-Vance

Research output: Contribution to journalArticlepeer-review

25 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)


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