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  1. Article ; Online: A comparative medical genomics approach may facilitate the interpretation of rare missense variation.

    Haque, Bushra / Guirguis, George / Curtis, Meredith / Mohsin, Hera / Walker, Susan / Morrow, Michelle M / Costain, Gregory

    Journal of medical genetics

    2024  

    Abstract: Purpose: To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context.: Methods: We extracted missense variants from the Online ... ...

    Abstract Purpose: To determine the degree to which likely causal missense variants of single-locus traits in domesticated species have features suggestive of pathogenicity in a human genomic context.
    Methods: We extracted missense variants from the Online Mendelian Inheritance in Animals database for nine animals (cat, cattle, chicken, dog, goat, horse, pig, rabbit and sheep), mapped coordinates to the human reference genome and annotated variants using genome analysis tools. We also searched a private commercial laboratory database of genetic testing results from >400 000 individuals with suspected rare disorders.
    Results: Of 339 variants that were mappable to the same residue and gene in the human genome, 56 had been previously classified with respect to pathogenicity: 31 (55.4%) pathogenic/likely pathogenic, 1 (1.8%) benign/likely benign and 24 (42.9%) uncertain/other. The odds ratio for a pathogenic/likely pathogenic classification in ClinVar was 7.0 (95% CI 4.1 to 12.0, p<0.0001), compared with all other germline missense variants in these same 220 genes. The remaining 283 variants disproportionately had allele frequencies and REVEL scores that supported pathogenicity.
    Conclusion: Cross-species comparisons could facilitate the interpretation of rare missense variation. These results provide further support for comparative medical genomics approaches that connect big data initiatives in human and veterinary genetics.
    Language English
    Publishing date 2024-03-20
    Publishing country England
    Document type Journal Article
    ZDB-ID 220881-7
    ISSN 1468-6244 ; 0022-2593
    ISSN (online) 1468-6244
    ISSN 0022-2593
    DOI 10.1136/jmg-2023-109760
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: Estimating the proportion of nonsense variants undergoing the newly described phenomenon of manufactured splice rescue.

    Haque, Bushra / Cheerie, David / Birkadze, Saba / Xu, Alice Linyan / Nalpathamkalam, Thomas / Thiruvahindrapuram, Bhooma / Walker, Susan / Costain, Gregory

    European journal of human genetics : EJHG

    2023  Volume 32, Issue 2, Page(s) 238–242

    Abstract: A recent report described a nonsense variant simultaneously creating a donor splice site, resulting in a truncated but functional protein. To explore the generalizability of this unique mechanism, we annotated >115,000 nonsense variants using SpliceAI. ... ...

    Abstract A recent report described a nonsense variant simultaneously creating a donor splice site, resulting in a truncated but functional protein. To explore the generalizability of this unique mechanism, we annotated >115,000 nonsense variants using SpliceAI. Between 0.61% (donor gain delta score >0.8, for high precision) and 2.57% (>0.2, for high sensitivity) of nonsense variants were predicted to create new donor splice sites at or upstream of the stop codon. These variants were less likely than other nonsense variants in the same genes to be classified as pathogenic/likely pathogenic in ClinVar (p < 0.001). Up to 1 in 175 nonsense variants were predicted to result in small in-frame deletions and loss-of-function evasion through this "manufactured splice rescue" mechanism. We urge caution when interpreting nonsense variants where manufactured splice rescue is a strong possibility and correlation with phenotype is challenging, as will often be the case with secondary findings and newborn genomic screening programs.
    MeSH term(s) Infant, Newborn ; Humans ; Codon, Nonsense ; Codon, Terminator ; Genomics ; Phenotype ; RNA Splice Sites/genetics
    Chemical Substances Codon, Nonsense ; Codon, Terminator ; RNA Splice Sites
    Language English
    Publishing date 2023-11-27
    Publishing country England
    Document type Journal Article
    ZDB-ID 1141470-4
    ISSN 1476-5438 ; 1018-4813
    ISSN (online) 1476-5438
    ISSN 1018-4813
    DOI 10.1038/s41431-023-01495-6
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Contemporary aetiologies of medical complexity in children: a cohort study.

    Haque, Bushra / Khan, Tayyaba / Ushcatz, Inna / Curtis, Meredith / Pan, Amy / Wu, Wendy / Orkin, Julia / Costain, Gregory

    Archives of disease in childhood

    2022  Volume 108, Issue 2, Page(s) 147–149

    MeSH term(s) Child ; Humans ; Cohort Studies ; Causality
    Language English
    Publishing date 2022-12-09
    Publishing country England
    Document type Letter ; Research Support, Non-U.S. Gov't
    ZDB-ID 524-1
    ISSN 1468-2044 ; 0003-9888 ; 1359-2998
    ISSN (online) 1468-2044
    ISSN 0003-9888 ; 1359-2998
    DOI 10.1136/archdischild-2022-325094
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  4. Article ; Online: A systematic assessment of the impact of rare canonical splice site variants on splicing using functional and in silico methods.

    Oh, Rachel Y / Almail, Ali / Cheerie, David / Guirguis, George / Hou, Huayun / Yuki, Kyoko E / Haque, Bushra / Thiruvahindrapuram, Bhooma / Marshall, Christian R / Mendoza-Londono, Roberto / Shlien, Adam / Kyriakopoulou, Lianna G / Walker, Susan / Dowling, James J / Wilson, Michael D / Costain, Gregory

    HGG advances

    2024  , Page(s) 100299

    Abstract: Background/objectives: Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to ACMG criterion PVS1). The exact nature and predictability of splicing ... ...

    Abstract Background/objectives: Canonical splice site variants (CSSVs) are often presumed to cause loss-of-function (LoF) and are assigned very strong evidence of pathogenicity (according to ACMG criterion PVS1). The exact nature and predictability of splicing effects of unselected rare CSSVs in blood-expressed genes is poorly understood.
    Methods: 168 rare CSSVs in unselected blood-expressed genes were identified by genome sequencing in 112 individuals, and their impact on splicing was interrogated manually in RNA sequencing (RNA-seq) data. Blind to these RNA-seq data, we attempted to predict the precise impact of CSSVs by applying in silico tools and the ClinGen Sequence Variant Interpretation Working Group 2018 guidelines for applying PVS1 criterion.
    Results: There was no evidence of a frameshift nor of reduced expression consistent with nonsense-mediated decay for 25.6% of CSSVs: 17.9% had wildtype splicing only and normal junction depths, 3.6% resulted in cryptic splice site usage and in-frame indels, 3.6% resulted in full exon skipping (in-frame), and 0.6% resulted in full intron inclusion (in-frame). The predicted impact on splicing using (i) SpliceAI, (ii) MaxEntScan, and (iii) AutoPVS1, an automatic classification tool for PVS1 interpretation of null variants that utilizes Ensembl Variant Effect Predictor and MaxEntScan, was concordant with RNA-seq analyses for 65%, 63% and 61% of CSSVs, respectively.
    Conclusion: Approximately 1 in 4 rare CSSVs may not cause LoF based on analysis of RNA-seq data. Predictions from in silico methods were often discordant with findings from RNA-seq. More caution may be warranted in applying PVS1-level evidence to CSSVs in the absence of functional data.
    Language English
    Publishing date 2024-04-23
    Publishing country United States
    Document type Journal Article
    ISSN 2666-2477
    ISSN (online) 2666-2477
    DOI 10.1016/j.xhgg.2024.100299
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Genome-wide tandem repeat expansions contribute to schizophrenia risk.

    Mojarad, Bahareh A / Engchuan, Worrawat / Trost, Brett / Backstrom, Ian / Yin, Yue / Thiruvahindrapuram, Bhooma / Pallotto, Linda / Mitina, Aleksandra / Khan, Mahreen / Pellecchia, Giovanna / Haque, Bushra / Guo, Keyi / Heung, Tracy / Costain, Gregory / Scherer, Stephen W / Marshall, Christian R / Pearson, Christopher E / Bassett, Anne S / Yuen, Ryan K C

    Molecular psychiatry

    2022  Volume 27, Issue 9, Page(s) 3692–3698

    Abstract: Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in ... ...

    Abstract Tandem repeat expansions (TREs) can cause neurological diseases but their impact in schizophrenia is unclear. Here we analyzed genome sequences of adults with schizophrenia and found that they have a higher burden of TREs that are near exons and rare in the general population, compared with non-psychiatric controls. These TREs are disproportionately found at loci known to be associated with schizophrenia from genome-wide association studies, in individuals with clinically-relevant genetic variants at other schizophrenia loci, and in families where multiple individuals have schizophrenia. We showed that rare TREs in schizophrenia may impact synaptic functions by disrupting the splicing process of their associated genes in a loss-of-function manner. Our findings support the involvement of genome-wide rare TREs in the polygenic nature of schizophrenia.
    MeSH term(s) Adult ; Humans ; Schizophrenia/genetics ; Schizophrenia/epidemiology ; Genome-Wide Association Study ; Genetic Predisposition to Disease/genetics ; Multifactorial Inheritance/genetics ; Tandem Repeat Sequences ; Polymorphism, Single Nucleotide/genetics
    Language English
    Publishing date 2022-05-12
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1330655-8
    ISSN 1476-5578 ; 1359-4184
    ISSN (online) 1476-5578
    ISSN 1359-4184
    DOI 10.1038/s41380-022-01575-x
    Database MEDical Literature Analysis and Retrieval System OnLINE

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