The typical familial form of Alzheimer's disease (FAD) accounts for about 5% of total Alzheimer's disease (AD) cases. Presenilins (PSEN1 and PSEN2) and amyloid-β (A4) precursor protein (APP) genes carry all reported FAD-linked mutations. However, other genetic loci may be involved in AD. For instance, seizure-related gene 6 (SEZ6) has been reported in brain development and psychiatric disorders and is differentially expressed in the cerebrospinal fluid of AD cases. We describe a targeted exome

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... equencing analysis of a large Italian kindred with AD, negative for PSEN and APP variants, that indicated the SEZ6 heterozygous mutation R615H is associated with the pathology. We overexpressed R615H mutation in H4-SW cells, finding a reduction of amyloid peptide Aβ(1-42). Sez6 expression decreased with age in a mouse model of AD (3xTG-AD), but independently from transgene expression. These results support a role of exome sequencing for disease-associated variant discovery and reinforce available data on SEZ6 in AD models.