Exome sequencing identifies rare damaging variants in ATP8B4 and ABCA1 as risk factors for Alzheimer's disease.

Alzheimer's disease (AD), the leading cause of dementia, has an estimated heritability of approximately 70%. The genetic component of AD has been mainly assessed using genome-wide association studies, which do not capture the risk contributed by rare variants. Here, we compared the gene-based burden of rare damaging variants in exome sequencing data from 32,558 individuals-16,036 AD cases and 16,522 controls.

SORL1 deficiency in human excitatory neurons causes APP-dependent defects in the endolysosome-autophagy network.

Dysfunction of the endolysosomal-autophagy network is emerging as an important pathogenic process in Alzheimer's disease. Mutations in the sorting receptor-encoding gene SORL1 cause autosomal-dominant Alzheimer's disease, and SORL1 variants increase risk for late-onset AD. To understand the contribution of SORL1 mutations to AD pathogenesis, we analyze the effects of a SORL1 truncating mutation on SORL1 protein levels and endolysosome function in human neurons.

Hypomyelination and congenital cataract: broadening the clinical phenotype.

Objective: To further delineate the clinical spectrum of hypomyelination and congenital cataract (HCC), a rare autosomal recessive white matter disorder due to deficiency of a membrane protein, hyccin, encoded by FAM126A.

Design: Case reports and literature review.

Setting: University hospital.

Large genomic deletions and duplications in the BRCA1 gene identified by a novel quantitative method.

We applied a novel method to detect single or multiple exon deletions and amplifications in the BRCA1 gene. The test, called multiplex ligation-dependent probe amplification (MLPA), uses probes designed to hybridize adjacently to the target sequence. After ligation, the joined probes are amplified and quantified.