Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases

Papadimitriou, Sofia; Gravel, Barbara; Nachtegael, Charlotte; Baere, Elfride De; Loeys, Bart; Vikkula, Miikka; Smits, Guillaume; Lenaerts, Tom

doi:10.1016/j.xhgg.2022.100165

Cited by 7 publications

(6 citation statements)

References 32 publications

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“…Phenotypically, only the son has anosmia, cleft lip and palate. Although our study might be criticised for possibility of FGFR1 monogenic disease model with coincidental presence of the identified PROKR2 variant in the patient or a lack of functional analysis of these mutations in vitro and in silico, 25 the identification of this additional mutation in PROKR2 raises intriguing questions regarding its role as a modifier gene and its potential contribution to the distinct phenotypic manifestations of KS and nCHH within the same family.…”

Section: Discussionmentioning

confidence: 97%

Additional mutation inPROKR2and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carryingFGFR1missense mutation

Ichioka,

Yoshikawa,

Kimura

et al. 2024

BMJ Case Rep

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Congenital hypogonadotropic hypogonadism (CHH) is a genetically and clinically diverse disorder encompassing Kallmann syndrome (KS) and normosmic CHH (nCHH). Although mutations in numerous genes account for nearly 50% of CHH cases, a significant portion remains genetically uncharacterized. While most mutations follow the traditional Mendelian inheritance patterns, evidence suggests oligogenic interactions between CHH genes, acting as modifier genes to explain variable expressivity and incomplete penetrance associated with certain mutations.In this study, the proband presented with nCHH, while his son exhibited KS. We employed whole-exome sequencing (WES) to investigate the genetic differences between the two, and Sanger sequencing was used to validate the results obtained from WES.Genetic analysis revealed that both the proband and his son harboured a mutation inFGFR1gene. Notably, an additional rare mutation inPROKR2gene was exclusively identified in the son, which suggests the cause of the phenotypic difference between KS and nCHH.

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Section: Discussionmentioning

confidence: 97%

Additional mutation inPROKR2and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carryingFGFR1missense mutation

Ichioka,

Yoshikawa,

Kimura

et al. 2024

BMJ Case Rep

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“…This does not diminish the usefulness of existing monogenic approaches, but rather highlights not only the need to design tools specifically for this task, but also the importance of scoring pathogenicity of variant combinations using method trained on oligogenic disease cases. Indeed, variants involved in oligogenic combinations have been shown to have different characteristics than variants involved in monogenic diseases, such as higher MAF and lower monogenic pathogenicity scores for both digenic and modifier variants ( Gazzo et al 2017 , Versbraegen et al 2019 , Papadimitriou et al 2023 ). Hop also introduces a new method to score the disease-relevance of gene pairs, combining the scores of the RWR algorithm to obtain a gene-pair proximity score to a set of disease-related seeds.…”

Section: Discussionmentioning

confidence: 99%

Prioritization of oligogenic variant combinations in whole exomes

Gravel,

Renaux,

Papadimitriou

et al. 2024

Bioinformatics

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Motivation Whole exome sequencing (WES) has emerged as a powerful tool for genetic research, enabling the collection of a tremendous amount of data about human genetic variation. However, properly identifying which variants are causative of a genetic disease remains an important challenge, often due to the number of variants that need to be screened. Expanding the screening to combinations of variants in two or more genes, as would be required under the oligogenic inheritance model, simply blows this problem out of proportion. Results We present here the High-throughput oligogenic prioritizer (Hop), a novel prioritization method that uses direct oligogenic information at the variant, gene and gene pair level to detect digenic variant combinations in WES data. This method leverages information from a knowledge graph, together with specialized pathogenicity predictions in order to effectively rank variant combinations based on how likely they are to explain the patient’s phenotype. The performance of Hop is evaluated in cross-validation on 36120 synthetic exomes for training and 14280 additional synthetic exomes for independent testing. Whereas the known pathogenic variant combinations are found in the top 20 in approximately 60% of the cross-validation exomes, 71% are found in the same ranking range when considering the independent set. These results provide a significant improvement over alternative approaches that depend simply on a monogenic assessment of pathogenicity, including early attempts for digenic ranking using monogenic pathogenicity scores. Availability Hop is available at https://github.com/oligogenic/HOP. Supplementary information Supplementary data are available at Bioinformatics online.

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“…As a result of the constructed feature representation of the model and the limited amount of higher-order oligogenic cases involving more genes with confident pathogenic evidence that are currently present in OLIDA [ 44 ], VarCoPP2.0 remains constrained to the prediction of bilocus variant combinations. However, the ORVAL platform [ 13 ], where VarCoPP2.0 is integrated, allows for the exploration of oligogenic networks that may involve more than two genes, by linking gene pairs containing predicted pathogenic variant combinations.…”

Section: Discussionmentioning

confidence: 99%

Faster and more accurate pathogenic combination predictions with VarCoPP2.0

et al. 2023

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Background The prediction of potentially pathogenic variant combinations in patients remains a key task in the field of medical genetics for the understanding and detection of oligogenic/multilocus diseases. Models tailored towards such cases can help shorten the gap of missing diagnoses and can aid researchers in dealing with the high complexity of the derived data. The predictor VarCoPP (Variant Combinations Pathogenicity Predictor) that was published in 2019 and identified potentially pathogenic variant combinations in gene pairs (bilocus variant combinations), was the first important step in this direction. Despite its usefulness and applicability, several issues still remained that hindered a better performance, such as its False Positive (FP) rate, the quality of its training set and its complex architecture. Results We present VarCoPP2.0: the successor of VarCoPP that is a simplified, faster and more accurate predictive model identifying potentially pathogenic bilocus variant combinations. Results from cross-validation and on independent data sets reveal that VarCoPP2.0 has improved in terms of both sensitivity (95% in cross-validation and 98% during testing) and specificity (5% FP rate). At the same time, its running time shows a significant 150-fold decrease due to the selection of a simpler Balanced Random Forest model. Its positive training set now consists of variant combinations that are more confidently linked with evidence of pathogenicity, based on the confidence scores present in OLIDA, the Oligogenic Diseases Database (https://olida.ibsquare.be). The improvement of its performance is also attributed to a more careful selection of up-to-date features identified via an original wrapper method. We show that the combination of different variant and gene pair features together is important for predictions, highlighting the usefulness of integrating biological information at different levels. Conclusions Through its improved performance and faster execution time, VarCoPP2.0 enables a more accurate analysis of larger data sets linked to oligogenic diseases. Users can access the ORVAL platform (https://orval.ibsquare.be) to apply VarCoPP2.0 on their data.

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Toward reporting standards for the pathogenicity of variant combinations involved in multilocus/oligogenic diseases

Cited by 7 publications

References 32 publications

Additional mutation inPROKR2and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carryingFGFR1missense mutation

Additional mutation inPROKR2and phenotypic differences in a Kallmann syndrome/normosmic congenital hypogonadotropic hypogonadism family carryingFGFR1missense mutation

Prioritization of oligogenic variant combinations in whole exomes

Faster and more accurate pathogenic combination predictions with VarCoPP2.0

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