Carriers of Heterozygous Loss-of-Function ACE Mutations Are at Risk for Alzheimer's Disease.

We hypothesized that subjects with heterozygous loss-of-function (LoF) mutations are at risk for Alzheimer's disease because amyloid Aβ42, a primary component of the protein aggregates that accumulate in the brains of AD patients, is cleaved by ACE (angiotensin I-converting enzyme). Thus, decreased ACE activity in the brain, either due to genetic mutation or the effects of ACE inhibitors, could be a risk factor for AD. To explore this hypothesis in the current study, existing SNP databases were analyzed for LoF mutations using four predicting tools, including PolyPhen-2, and compared with the topology of known mutations already associated with AD.

DeMAG predicts the effects of variants in clinically actionable genes by integrating structural and evolutionary epistatic features.

Despite the increasing use of genomic sequencing in clinical practice, the interpretation of rare genetic variants remains challenging even in well-studied disease genes, resulting in many patients with Variants of Uncertain Significance (VUSs). Computational Variant Effect Predictors (VEPs) provide valuable evidence in variant assessment, but they are prone to misclassifying benign variants, contributing to false positives. Here, we develop Deciphering Mutations in Actionable Genes (DeMAG), a supervised classifier for missense variants trained using extensive diagnostic data available in 59 actionable disease genes (American College of Medical Genetics and Genomics Secondary Findings v2.

Informing variant assessment using structured evidence from prior classifications (PS1, PM5, and PVS1 sequence variant interpretation criteria).

Purpose: This study aimed to explore whether evidence of pathogenicity from prior variant classifications in ClinVar could be used to inform variant interpretation using the American College of Medical Genetics and Genomics/Association for Molecular Pathology clinical guidelines.

Methods: We identified distinct single-nucleotide variants (SNVs) that are either similar in location or in functional consequence to pathogenic variants in ClinVar and analyzed evidence in support of pathogenicity using 3 interpretation criteria.

Results: Thousands of variants, including many in clinically actionable disease genes (American College of Medical Genetics and Genomics secondary findings v3.

Erratum.

This corrects the article on p. e1000281 in Vol. 4, PMID: 19043566.

Hypermutable non-synonymous sites are under stronger negative selection.

Mutation rate varies greatly between nucleotide sites of the human genome and depends both on the global genomic location and the local sequence context of a site. In particular, CpG context elevates the mutation rate by an order of magnitude. Mutations also vary widely in their effect on the molecular function, phenotype, and fitness.

A universal trend of amino acid gain and loss in protein evolution.

Amino acid composition of proteins varies substantially between taxa and, thus, can evolve. For example, proteins from organisms with (G + C)-rich (or (A + T)-rich) genomes contain more (or fewer) amino acids encoded by (G + C)-rich codons. However, no universal trends in ongoing changes of amino acid frequencies have been reported.