About Mutations

Methods

The Alzforum Mutations database aggregates information about genetic variants reported in the literature. This database focuses on a subset of genes implicated in Alzheimer’s disease. We started out by curating variants in genes associated with autosomal-dominant AD, and then broadened the scope to include variants in genes linked to AD in other ways, such as through association studies (TREM2) or pathology (MAPT). We take a “gene-centric” approach, with the goal of cataloguing all reported variants identified in patients, families, or controls, regardless of whether the variant is thought to be pathogenic, not pathogenic, or somewhere in between, i.e., modifying a person’s risk of developing AD.

Inclusion Criteria

All variants in included genes (currently APP, PSEN1, PSEN2, MAPT, TREM2) are eligible for inclusion, whether they were reported in a peer-reviewed publication, a meeting abstract, a review, or by personal communication.

Data Sources

Information is curated from the published literature, primarily peer-reviewed scientific articles. Review articles and book chapters are also sources. When no peer-reviewed publication is available, we occasionally include findings reported in conference abstracts. In addition, authors provide information to Alzforum via personal communication. Within the database, some papers are identified as “primary papers”; these are generally the first paper(s) to identify a variant.

Curation Strategy

We monitor the literature weekly for new variants and new information about existing variants. While we aim to include all eligible information, we prioritize novel mutations over newly identified carriers of previously identified variants. We also prioritize variants identified as pathogenic, risk modifiers, or possible risk modifiers, over nonpathogenic or unclear variants. Our variant descriptions summarize the evidence for genetic association with disease, clinical findings, neuropathology/imaging, and reported biological effects. We extract this information from the primary papers, follow-up papers, and other sources, consulting with authors for clarification as needed. 

Pathogenicity Classification

Determining which variants play a role in disease and which are benign is a big challenge in neurogenetics. There are efforts in the field to devise systematic approaches to assess the pathogenicity of variants, allowing for a more standardized, objective method of classifying variants based on the available evidence (e.g., Guerreiro et al., 2010). However, there are no universally agreed-upon criteria for classifying pathogenicity.

Within this database, variants are classified as pathogenic, nonpathogenic, protective, or unclear. Some variants, primarily those within TREM2, are classified as risk modifiers or possible risk modifiers. In addition, a given variant may be classified as a risk modifier for one disease and a possible risk modifier for other diseases. For example, TREM2 R47H is classified as a risk modifier for AD and a possible risk modifier for PD, FTD, and ALS. Currently, variants in the database are classified according to the curator’s synthesis of the available evidence, as described below. As new information emerges over time, variants may be reclassified (see Aug 2012 webinar).

Complicating classification is the finding that the prevalence of variants is different from one population to the next, being extremely rare, or even absent, in some populations. In addition, it is possible that a person’s genetic background may influence the pathogenicity of a particular variant. We curate information on the country of origin and/or the ethnicity of the individual or cohort into the database when available.

Pathogenicity Terms

• Pathogenic
A variant is classified as pathogenic for a disease when it segregates with the disease phenotype within a family. However, evidence of segregation is not always available, for example when the genotype of unaffected family members is unknown. In this case, the curator evaluates the supporting evidence for pathogenicity. Such evidence may include: multiple affected variant carriers, a clear family history of disease in an affected carrier, absence of the variant in healthy controls (in diseases exhibiting a recessive pattern of inheritance, controls may be heterozygous), in silico predictions of protein function, and experimental evidence of a pathobiological effect. In some cases, variants may be classified as pathogenic, even if one or more carriers are healthy (e.g., APP E693del). If the preponderance of the evidence suggests a variant is pathogenic, an unaffected carrier may be an example of incomplete penetrance or be considered an "escapee," i.e., a variant carrier who remained healthy beyond the family’s average age of onset.

• Risk Modifier
A variant is classified as a risk modifier when a preponderance of evidence supports an association to the disease. For example, the R62H variant in TREM2 is classified as a risk modifier based largely upon the strength of a single study involving a large number of individuals, which reported a genome-wide significant association. In cases where a large, definitive study is unavailable, a variant may be classified as a risk modifier when the number of studies reporting an association exceeds the number that do not.

• Possible Risk Modifier
A variant is classified as a possible risk modifier when one or more studies support an association, but at least an equal number do not. The “possible” designation does not imply a specific degree of confidence, and could range from unlikely to probable.

• Protective 
A variant is classified as protective when it is more prevalent in cognitively healthy individuals than in those with AD. This classification may be further supported by in silico predictions or experimental evidence of beneficial effects.

• Nonpathogenic
A variant is classified as nonpathogenic if it does not appear to cause disease; in other words, it does not segregate with disease or meet other criteria for a pathogenic, risk modifier, or possible risk-modifier classification (see above).

• Unclear
A variant is classified as unclear when, in the judgement of the curator, conflicting evidence exists regarding the role of the variant in disease, preventing classification into one of the above categories. A variant may also be classified as unclear in cases in which there is insufficient data to make a classification.

Reference Isoforms

By convention, variants are named according to their amino acid position in a reference isoform. The reference isoform is not necessarily the canonical sequence. In cases where the reference isoform does not include the variant, such as variants that are in exons excluded from the reference isoform by alternative splicing, the variant is named according to its position in an isoform in which it is found. For example, TREM2 W191X is found only in the shortest TREM2 transcript; the “191” in its name refers to amino acid 191 encoded by that transcript, not the 191st amino acid in the reference isoform. When a variant is reported in the literature by its position in a non-reference isoform, but is present in the reference isoform, Alzforum standardizes its name to the reference isoform.

Gene Reference Reference Isoform Amino Acids Uniprot ID
APP Isoform 770 770 AA P05067
PSEN1 Isoform 1 467 AA P49768
PSEN2 Isoform 1 448 AA P49810
MAPT Isoform 441, Tau-F, Tau4 441 AA P10636-8
TREM2 Isoform 1 230 AA Q9NZC2-1