Proteins linked to autosomal dominant and autosomal recessive disorders harbor characteristic rare missense mutation distribution patterns

Abstract

The role of rare missense variants in disease causation remains difficult to interpret. We explore whether the clustering pattern of rare missense variants (MAF < 0.01) in a protein is associated with mode of inheritance. Mutations in genes associated with autosomal dominant (AD) conditions are known to result in either loss or gain of function, whereas mutations in genes associated with autosomal recessive (AR) conditions invariably result in loss-of-function. Loss-of-function mutations tend to be distributed uniformly along protein sequence, whereas gain-of-function mutations tend to localize to key regions. It has not previously been ascertained whether these patterns hold in general for rare missense mutations. We consider the extent to which rare missense variants are located within annotated protein domains and whether they form clusters, using a new unbiased method called CLUstering by Mutation Position. These approaches quantified a significant difference in clustering between AD and AR diseases. Proteins linked to AD diseases exhibited more clustering of rare missense mutations than those linked to AR diseases (Wilcoxon P = 5.7 × 10 −4 , permutation P = 8.4 × 10 −4). Rare missense mutation in proteins linked to either AD or AR diseases was more clustered than controls (1000G) (Wilcoxon P = 2.8 × 10 −15 for AD and P = 4.5 × 10 −4 for AR, permutation P = 3.1 × 10 −12 for AD and P = 0.03 for AR). The differences in clustering patterns persisted even after removal of the most prominent genes. Testing for such non-random patterns may reveal novel aspects of disease etiology in large sample studies.

Reassessment of Mendelian gene pathogenicity using 7,855 cardiomyopathy cases and 60,706 reference samples

“…This may be improved by considering protein topology, as pathogenic variants often cluster in specific regions in cases31,32. We evaluated the distribution of rare missense alleles in MYH7 , which encodes a protein with well-characterised functional and structural domains, to assess whether systematic analysis of variant distribution refines interpretation.…”

denovo-db: a compendium of humande novovariants

“…This provides the research community with a one-stop location for assessing the significance of particular genes or mutations as they relate to their phenotype of interest. The researcher could then ask questions relevant to a disease, such as whether the number of de novo variants seen in a gene is statistically significant using tools such as denovolyzeR (20), or one could ask whether the variants seen in a gene, across many individuals, are more clustered in disease than would be expected based on control data using tools such as CLUMP (21). A researcher could also ask questions unrelated to disease with patterns of de novo variants gathered across many individuals potentially providing novel insight into the biology of new mutation in the human genome.…”

Clinical and radiological findings in a severe case of cleidocranial dysplasia

“…In autosomal dominant inheritance, the affected individual inherits the mutated gene from the affected parent or it could totally be a new mutation in the gene, which could later account in passing the affected gene to their offspring 4. Diseases affected by autosomal dominance are due to the mutation in the confined set of amino acid residues with only specific effect on the functioning of the protein component 5. It was reported that about one-third of the CCD is caused by new mutation without either of the parents being affected and the remaining two-thirds of the cases are caused by the inherited gene from the parent 6.…”