Send to

Choose Destination
J Alzheimers Dis Parkinsonism. 2017 Aug;7(4). pii: 355. doi: 10.4172/2161-0460.1000355. Epub 2017 Jul 31.

Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function.

Author information

John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
Department of Neurology, University of Miami Miller School of Medicine, Miami, FL, USA.
John T. Macdonald Foundation, Department of Human Genetics, University of Miami Miller School of Medicine, Miami, FL, USA.
Mental Health and Behavioral Sciences Service, Miami Veterans Affairs, Miami, FL, USA.
Departments of Medicine, Neurology, Ophthalmology, Genetics and Genomics, Epidemiology and Biostatistics, Boston University, Boston, MA, USA.
Department of Population and Quantitative Health Sciences, Case Western Reserve University, Cleveland, OH, USA.



Alzheimer's disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD.


Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized.


Rare variants were found in known AD risk genes including AKAP9, CD33, CR1, EPHA1, INPP5D, NME8, PSEN1, SORL1, TREM2 and UNC5C. Three families had five variants of interest in linkage regions with LOD>2. Genes with segregating alterations in these peaks include CD163L1 and CLECL1, two genes that have both been implicated in immunity, CTNNA1, which encodes a catenin in the cerebral cortex and MIEF1, a gene that may induce mitochondrial dysfunction and has the potential to damage neurons. Four genes were identified with alterations in more than one family include PLEKHG5, a gene that causes Charcot-Marie-Tooth disease and THBS2, which promotes synaptogenesis.


Utilizing large families with a heavy burden of disease allowed for the identification of rare variants co-segregating with disease. Variants were identified in both known AD risk genes and in novel genes.


Alzheimer’s disease; dominant inheritance; linkage; multiplex; whole exome sequencing

Supplemental Content

Full text links

Icon for PubMed Central
Loading ...
Support Center