Improvement of MEFV gene variants classification to aid treatment decision making in familial Mediterranean fever

Abstract

Objective FMF is an inherited autoinflammatory syndrome caused by mutations in the MEFV gene. MEFV variants are still largely classified as acvariant of uncertain significance, or with unresolved classification, posing significant challenges in FMF diagnosis. Rare Exome Variant Ensemble Learner (REVEL) is a recently developed variant metapredictor tool. To reduce the number of MEFV variants with ambiguous classification, we extracted REVEL scores for all missense variants present in the INFEVERS database, and analysed its correlation with expert-based classification and localization in the MEFV-encoded pyrin functional domains. Methods The data set of 216 MEFV missense variants was divided into four categories (likely benign, variant of uncertain significance, likely pathogenic and unresolved). Variants were plotted onto the pyrin protein, the distribution of REVEL scores in each category was computed and means, confidence intervals, and area under the receiver operating curve were calculated. Results We observed a non-random distribution of pathogenic variants along the pyrin functional domains. The REVEL scores demonstrated a good correlation with the consensus classification of the International Study Group for Systemic Autoinflammatory Diseases. Sensitivity, specificity and accuracy were calculated for different cut-off values of REVEL scores and a gene-specific-threshold of 0.298 was computed with confidence boundary limits. This cut-off value allowed us to propose a reclassification of 96 MEFV gene variants, thus reducing the variant of uncertain significance proportion from 61.6% to 17.6%. Conclusion The combination of available expert information with sensitive predictor tools could result in a more accurate interpretation of clinical consequences of MEFV gene variants, and to a better genetic counselling and patient management.

In-silico Analysis of NF1 Missense Variants in ClinVar: Translating Variant Predictions into Variant Interpretation and Classification

“…Next, we aimed to reduce the number of VUS variants (88% of the dataset) with the same strategy already utilized to improve MEFV gene variants classification in Familial Mediterranean Fever (FMF), a disease where clinical misdiagnosis can be as frequent as in NF1 [53].…”

Distinguishing between recent balancing selection and incomplete sweep using deep neural networks

“…where most of the FMF-causing variants cluster [71] shows the same genetic patterns of ongoing selection.…”

Familial Mediterranean Fever and COVID-19: Friends or Foes?

“…This region may have an autoinhibitory role precluding the PYD domain from interacting with ASC and activating pyroptosis (38). The C-terminal B30.2 (also known as PRY/SPRY) domain is extremely important in FMF pathogenesis since most of the disease-penetrant MEFV variants cluster in this region (39). Although this uneven distribution of FMF-associated MEFV mutations suggests that the B30.2 domain is crucial in regulating Pyrin inflammasome activity, the precise molecular mechanisms by which the B30.2 domain regulates FMF pathogenesis have not been elucidated (40).…”