# Molecular Origins of the Mendelian Rare Diseases Reviewed by Orpha.net: A Structural Bioinformatics Investigation

## TL;DR

This study uses structural bioinformatics to explore how mutations cause rare genetic diseases, offering insights into their molecular origins.

## Contribution

The paper introduces a structural analysis of pathogenic variants in proteins linked to Mendelian rare diseases using depth-dependent mutation site distributions.

## Key findings

- Pathogenic missense variants in MRD-related proteins show distinct distributions at different 3D protein depths.
- Depth-dependent effects of 20,061 pathogenic variants were identified, offering clues to mitigate MRD damage.
- Structural bioinformatics analysis of 2515 MRD proteins reveals molecular insights into rare disease origins.

## Abstract

The study of rare diseases is important not only for the individuals affected but also for the advancement of medical knowledge and a deeper understanding of human biology and genetics. The wide repertoire of structural information now available from reliable and accurate prediction methods provides the opportunity to investigate the molecular origins of most of the rare diseases reviewed in the Orpha.net database. Thus, it has been possible to analyze the topology of the pathogenic missense variants found in the 2515 proteins involved in Mendelian rare diseases (MRDs), which form the database for our structural bioinformatics study. The amino acid substitutions responsible for MRDs showed different mutation site distributions at different three-dimensional protein depths. We then highlighted the depth-dependent effects of pathogenic variants for the 20,061 pathogenic variants that are present in our database. The results of this structural bioinformatics investigation are relevant, as they provide additional clues to mitigate the damage caused by MRD.