Improved pathogenicity prediction for rare human missense variants

Wu, Yingzhou; Liu, Hanqing; Li, Roujia; Sun, Song; Weile, Jochen; Roth, Frederick P.

doi:10.1016/j.ajhg.2021.08.012

Cited by 91 publications

(80 citation statements)

References 69 publications

(245 reference statements)

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“…GRIA2 Ala643 is located at the lurcher site [17] in the highly conserved sequence (SYTANLA A F) that forms the upper AMPAR ion channel gate ( Fig 1f ). Bioinformatic predictions suggested that the variant was likely to be pathogenic – SIFT pathogenic, score 0 [18]; polyphen 2, probably damaging, score 0.999 [19]; VARITY R, score 0.953 [20]. Indeed, variants at this site have previously been suggested as disease-causing for GRIA1 [6], GRIA4 [4], and GRIA3 (present in ClinVar database) ( Fig 1f ).…”

Section: Resultsmentioning

confidence: 98%

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

Coombs

Ziobro

Krotov

et al. 2022

Preprint

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AMPA-type glutamate receptors (AMPARs) are tetrameric ligand-gated ion channels formed as different combinations of GluA1-4 subunits encoded by the genes GRIA1-4. Various pathogenic variants of these genes have been described in patients with developmental delay, intellectual disability, autistic spectrum disorder and seizures. Here we report a heterozygous de novo pathogenic missense mutation in GRIA2 (c.1928 C>T, p.A643V) identified in a one-year-old male patient with seizures, developmental delay and failure to thrive. Electrophysiological investigation of heterologously expressed receptors showed GluA2 A643V to exhibit greatly slowed deactivation, and a markedly reduced extent of desensitization, compared with wild-type GluA2. When GluA2 A643V was coexpressed with the transmembrane AMPAR regulatory protein (TARP) γ2, or with both GluA1 and γ2 to generate TARPed heteromeric receptors, the slowed deactivation and decreased desensitization persisted. We found that the AMPAR negative allosteric modulator perampanel was able to fully block currents from GluA2 A643V/γ2 receptors, albeit with reduced potency compared with wild-type GluA2/γ2. The introduction of perampanel to the patient’s treatment regimen, alongside a modified Atkins diet, was associated with a marked reduction in seizure number, a resolution of failure to thrive, and clear developmental gains. Our study suggests that AMPAR gain-of-function (GoF) underlies the effect of the GRIA2 variant in our patient, and that perampanel may be beneficial in other patients with GRIA GoF variants.Author summaryRapid communication between brain cells is mediated by the excitatory neurotransmitter glutamate. Mutations affecting genes that encode glutamate-gated ion channels can result in neurodevelopmental disorders and seizures. In a young male patient, we identified a mutation in the gene responsible for production of GluA2, a key subunit of AMPA-type glutamate receptors. We showed that receptors containing GluA2 produced by this GRIA2 A643V variant were more sensitive to glutamate and gave rise to unusually prolonged or sustained responses, thus causing ‘gain-of-function’. We found that receptors affected by this mutation could, nonetheless, be inhibited by the AMPA receptor-targeting antiseizure medication, perampanel. Prompted by this finding we introduced perampanel alongside the patient’s ongoing antiseizure medication. This coincided with a decrease in the patient’s seizures and clear developmental gains. Taken together, our findings suggest that a GRIA2 gain-of-function mutation can cause neurological disease, that perampanel can be used to directly counteract the effect of the mutation, and that it may be beneficial in other GRIA gain-of-function patients.

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Section: Resultsmentioning

confidence: 98%

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

Coombs

Ziobro

Krotov

et al. 2022

Preprint

View full text Add to dashboard Cite

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“…and/or other technical inaccuracies such as sequencing errors. More accurate variant effect prediction tools should further increase the power of these kinds of analyses 66,106,107 . We also found that using two techniques to derive informative somatic mutation phenotypes identified more replicated associations than using either approach alone.…”

Section: Discussionmentioning

confidence: 99%

The impact of rare germline variants on human somatic mutation processes

2022

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Somatic mutations are an inevitable component of ageing and the most important cause of cancer. The rates and types of somatic mutation vary across individuals, but relatively few inherited influences on mutation processes are known. We perform a gene-based rare variant association study with diverse mutational processes, using human cancer genomes from over 11,000 individuals of European ancestry. By combining burden and variance tests, we identify 207 associations involving 15 somatic mutational phenotypes and 42 genes that replicated in an independent data set at a false discovery rate of 1%. We associate rare inherited deleterious variants in genes such as MSH3, EXO1, SETD2, and MTOR with two phenotypically different forms of DNA mismatch repair deficiency, and variants in genes such as EXO1, PAXIP1, RIF1, and WRN with deficiency in homologous recombination repair. In addition, we identify associations with other mutational processes, such as APEX1 with APOBEC-signature mutagenesis. Many of the genes interact with each other and with known mutator genes within cellular sub-networks. Considered collectively, damaging variants in the identified genes are prevalent in the population. We suggest that rare germline variation in diverse genes commonly impacts mutational processes in somatic cells.

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“…M-CAP is based on a gradient boosting tree classifier model, and it applies 318 features as input into the model. MetaLR uses logistic regression to integrate nine independent variant deleteriousness scores [ 66 ]. PROVEAN is a prediction tool based on sequence clustering [ 67 ] to predict the modification of protein function due to amino acid substitution [ 68 , 69 ].…”

Section: Methodsmentioning

confidence: 99%

Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1

Choi

Mitra

Munni

et al. 2022

IJMS

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Disruptive neuronal migration during early brain development causes severe brain malformation. Characterized by mislocalization of cortical neurons, this condition is a result of the loss of function of migration regulating genes. One known neuronal migration disorder is lissencephaly (LIS), which is caused by deletions or mutations of the LIS1 (PAFAH1B1) gene that has been implicated in regulating the microtubule motor protein cytoplasmic dynein. Although this class of diseases has recently received considerable attention, the roles of non-synonymous polymorphisms (nsSNPs) in LIS1 on lissencephaly progression remain elusive. Therefore, the present study employed combined bioinformatics and molecular modeling approach to identify potential damaging nsSNPs in the LIS1 gene and provide atomic insight into their roles in LIS1 loss of function. Using this approach, we identified three high-risk nsSNPs, including rs121434486 (F31S), rs587784254 (W55R), and rs757993270 (W55L) in the LIS1 gene, which are located on the N-terminal domain of LIS1. Molecular dynamics simulation highlighted that all variants decreased helical conformation, increased the intermonomeric distance, and thus disrupted intermonomeric contacts in the LIS1 dimer. Furthermore, the presence of variants also caused a loss of positive electrostatic potential and reduced dimer binding potential. Since self-dimerization is an essential aspect of LIS1 to recruit interacting partners, thus these variants are associated with the loss of LIS1 functions. As a corollary, these findings may further provide critical insights on the roles of LIS1 variants in brain malformation.

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Improved pathogenicity prediction for rare human missense variants

Cited by 91 publications

References 69 publications

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

A gain-of-function GRIA2 variant associated with neurodevelopmental delay and seizures: functional characterization and targeted treatment

The impact of rare germline variants on human somatic mutation processes

Structural Consequence of Non-Synonymous Single-Nucleotide Variants in the N-Terminal Domain of LIS1

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