Neurol Genet 2016 Feb 14;2(1):e41. Epub 2016 Jan 14.
John P. Hussman Institute for Human Genomics (M.A.K., H.N.C., K.L.H.-N., S.R., B.W.K., P.L.W., S.L.Z., E.R.M., G.W.B., J.M.V., M.L.C., J.R.G., R.M.C., M.A.P.-V.), Department of Neurology (H.N.C., S.L.Z., J.M.V., M.A.P.-V.), and Dr. John T. Macdonald Foundation Department of Human Genetics (S.L.Z., E.R.M., G.W.B., J.M.V., M.L.C., J.R.G., M.A.P.-V.), University of Miami, Miller School of Medicine, Miami, FL; Departments of Medicine, Neurology, Ophthalmology, Genetics & Genomics, Epidemiology, and Biostatistics (L.A.F.), Boston University, Boston, MA; Department of Epidemiology and Biostatistics (J.L.H.), Institute for Computational Biology, Case Western Reserve University School of Medicine, Cleveland, OH; and Department of Pathology and Laboratory Medicine (G.D.S.), University of Pennsylvania School of Medicine, Philadelphia, PA.
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.