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  1. Fulltext GWAS signals revisited using human knockouts
    Maddirevula S, AlZahrani F, Anazi S, Almureikhi M, Ben-Omran T, Abdel-Salam GMH, et al.
    Genet Med, 2018 01;20(1):64-68.
    PMID: 28640246 DOI: 10.1038/gim.2017.78
    PurposeGenome-wide association studies (GWAS) have been instrumental to our understanding of the genetic risk determinants of complex traits. A common challenge in GWAS is the interpretation of signals, which are usually attributed to the genes closest to the polymorphic markers that display the strongest statistical association. Naturally occurring complete loss of function (knockout) of these genes in humans can inform GWAS interpretation by unmasking their deficiency state in a clinical context.MethodsWe exploited the unique population structure of Saudi Arabia to identify novel knockout events in genes previously highlighted in GWAS using combined autozygome/exome analysis.ResultsWe report five families with homozygous truncating mutations in genes that had only been linked to human disease through GWAS. The phenotypes observed in the natural knockouts for these genes (TRAF3IP2, FRMD3, RSRC1, BTBD9, and PXDNL) range from consistent with, to unrelated to, the previously reported GWAS phenotype.ConclusionWe expand the role of human knockouts in the medical annotation of the human genome, and show their potential value in informing the interpretation of GWAS of complex traits.
  2. Fulltext Expanding the phenome and variome of skeletal dysplasia
    Maddirevula S, Alsahli S, Alhabeeb L, Patel N, Alzahrani F, Shamseldin HE, et al.
    Genet Med, 2018 12;20(12):1609-1616.
    PMID: 29620724 DOI: 10.1038/gim.2018.50
    PURPOSE: To describe our experience with a large cohort (411 patients from 288 families) of various forms of skeletal dysplasia who were molecularly characterized.

    METHODS: Detailed phenotyping and next-generation sequencing (panel and exome).

    RESULTS: Our analysis revealed 224 pathogenic/likely pathogenic variants (54 (24%) of which are novel) in 123 genes with established or tentative links to skeletal dysplasia. In addition, we propose 5 genes as candidate disease genes with suggestive biological links (WNT3A, SUCO, RIN1, DIP2C, and PAN2). Phenotypically, we note that our cohort spans 36 established phenotypic categories by the International Skeletal Dysplasia Nosology, as well as 18 novel skeletal dysplasia phenotypes that could not be classified under these categories, e.g., the novel C3orf17-related skeletal dysplasia. We also describe novel phenotypic aspects of well-known disease genes, e.g., PGAP3-related Toriello-Carey syndrome-like phenotype. We note a strong founder effect for many genes in our cohort, which allowed us to calculate a minimum disease burden for the autosomal recessive forms of skeletal dysplasia in our population (7.16E-04), which is much higher than the global average.

    CONCLUSION: By expanding the phenotypic, allelic, and locus heterogeneity of skeletal dysplasia in humans, we hope our study will improve the diagnostic rate of patients with these conditions.

  3. Genetic abnormalities in a large cohort of Coffin-Siris syndrome patients
    Sekiguchi F, Tsurusaki Y, Okamoto N, Teik KW, Mizuno S, Suzumura H, et al.
    J Hum Genet, 2019 Dec;64(12):1173-1186.
    PMID: 31530938 DOI: 10.1038/s10038-019-0667-4
    Coffin-Siris syndrome (CSS, MIM#135900) is a congenital disorder characterized by coarse facial features, intellectual disability, and hypoplasia of the fifth digit and nails. Pathogenic variants for CSS have been found in genes encoding proteins in the BAF (BRG1-associated factor) chromatin-remodeling complex. To date, more than 150 CSS patients with pathogenic variants in nine BAF-related genes have been reported. We previously reported 71 patients of whom 39 had pathogenic variants. Since then, we have recruited an additional 182 CSS-suspected patients. We performed comprehensive genetic analysis on these 182 patients and on the previously unresolved 32 patients, targeting pathogenic single nucleotide variants, short insertions/deletions and copy number variations (CNVs). We confirmed 78 pathogenic variations in 78 patients. Pathogenic variations in ARID1B, SMARCB1, SMARCA4, ARID1A, SOX11, SMARCE1, and PHF6 were identified in 48, 8, 7, 6, 4, 1, and 1 patients, respectively. In addition, we found three CNVs including SMARCA2. Of particular note, we found a partial deletion of SMARCB1 in one CSS patient and we thoroughly investigated the resulting abnormal transcripts.
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