Attempts at using protein structures to identify disease-causing mutations have been dominated by the idea that most pathogenic mutations are disruptive at a structural level. Therefore, computational stability predictors, which assess whether a mutation is likely to be stabilising or destabilising to protein structure, have been commonly used when evaluating new candidate disease variants, despite not having been developed specifically for this purpose. We therefore tested 13 different stability predictors for their ability to discriminate between pathogenic and putatively benign missense variants. We find that one method, FoldX, significantly outperforms all other predictors in the identification of disease variants. Moreover, we demonstrate that employing predicted absolute energy change scores improves performance of nearly all predictors in distinguishing pathogenic from benign variants. Importantly, however, we observe that the utility of computational stability predictors is highly heterogeneous across different proteins, and that they are all inferior to the best performing variant effect predictors for identifying pathogenic mutations. We suggest that this is largely due to alternate molecular mechanisms other than protein destabilisation underlying many pathogenic mutations. Thus, better ways of incorporating protein structural information and molecular mechanisms into computational variant effect predictors will be required for improved disease variant prioritisation.

Most known disease-causing mutations occur in protein-coding regions of DNA. While some of these involve a loss of protein function (e.g., through premature stop codons or missense changes that destabilize protein folding), many act via alternative molecular mechanisms and have dominant-negative or gain-of-function effects. In nearly all cases, these non-loss-of-function mutations can be understood by considering interactions of the wild-type and mutant protein with other molecules, such as proteins, nucleic acids, or small ligands and substrates. Here, we review the diverse molecular mechanisms by which pathogenic mutations can have non-loss-of-function effects, including by disrupting interactions, increasing binding affinity, changing binding specificity, causing assembly-mediated dominant-negative and dominant-positive effects, creating novel interactions, and promoting aggregation and phase separation. We believe that increased awareness of these diverse molecular disease mechanisms will lead to improved diagnosis (and ultimately treatment) of human genetic disorders. Expected final online publication date for the Annual Review of Genomics and Human Genetics, Volume 23 is October 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

BackgroundImprovements in data processing, increased understanding of the biomechanical background behind kinetics and kinematics, and technological advancements in inertial measurement unit (IMU) sensors have enabled high precision in the measurement of joint angles and acceleration on human subjects. This has resulted in new devices that reportedly measure joint angles, arm speed, and stresses to the pitching arms of baseball players. This study seeks to validate one such sensor, the MotusBASEBALL unit, with a marker-based motion capture laboratory.HypothesisWe hypothesize that the joint angle measurements (“arm slot” and “shoulder rotation”) of the MotusBASEBALL device will hold a statistically significant level of reliability and accuracy, but that the “arm speed” and “stress” metrics will not be accurate due to limitations in IMU technology.MethodsA total of 10 healthy subjects threw five to seven fastballs followed by five to seven breaking pitches (slider or curveball) in the motion capture lab. Subjects wore retroreflective markers and the MotusBASEBALL sensor simultaneously.ResultsIt was found that the arm slot (R = 0.975, P < 0.001), shoulder rotation (R = 0.749, P < 0.001), and stress (R = 0.667, P = 0.001 when compared to elbow torque; R = 0.653, P = 0.002 when compared to shoulder torque) measurements were all significantly correlated with the results from the motion capture lab. Arm speed showed significant correlations to shoulder internal rotation speed (R = 0.668, P = 0.001) and shoulder velocity magnitude (R = 0.659, P = 0.002). For the entire sample, arm slot and shoulder rotation measurements were on a similar scale, or within 5–15% in absolute value, of magnitude to measurements from the motion capture test, averaging eight degrees less (12.9% relative differences) and nine degrees (5.4%) less, respectively. Arm speed had a much larger difference, averaging 3,745 deg/s (80.2%) lower than shoulder internal rotation velocity, and 3,891 deg/s (80.8%) less than the shoulder velocity magnitude. The stress metric was found to be 41 Newton meter (Nm; 38.7%) less when compared to elbow torque, and 42 Nm (39.3%) less when compared to shoulder torque. Despite the differences in magnitude, the correlations were extremely strong, indicating that the MotusBASEBALL sensor had high reliability for casual use.ConclusionThis study attempts to validate the use of the MotusBASEBALL for future studies that look at the arm slot, shoulder rotation, arm speed, and stress measurements from the MotusBASEBALL sensor. Excepting elbow extension velocity, all metrics from the MotusBASEBALL unit showed significant correlations to their corresponding metrics from motion capture and while some magnitudes differ substantially and therefore fall short in validity, the link between the metrics is strong enough to indicate reliable casual use. Further research should be done to further investigate the validity and reliability of the arm speed metric.