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    Intellectual developmental disorder with dysmorphic facies, seizures, and distal limb anomalies (IDDFSDA) is an autosomal recessive multisystem disorder caused by compound heterozygous or homozygous variants in the gene OTUD6B. Herein, we describe novel pathogenic compound heterozygous variants in OTUD6B identified via whole-exome sequencing in an index case exhibited the severe IDDFSDA phenotype. The potential pathogenicity of the novel frameshift and missense variants in the index case was investigated using in silico tools. The truncating frameshift variant in one allele was predicted to undergo degradation via nonsense-mediated decay of the mRNA molecule. To predict the severity of the damage to the protein caused by the missense variant in the other allele and its effects on phenotypic severity was further investigated together with a previously reported first homozygous missense variant in the same domain in another patient with a less severe IDDFSDA phenotype using structural modeling and molecular dynamics (MD) simulations for the first time. Based on these analyzes, it is anticipated that Tyr216Cys in the earlier reported case with less severe IDDFSDA will lead to localized destabilization, whereas Ile274Arg in the presented index case with the severe IDDFSDA phenotype will lead to significant distortion in the overall fold of OTUD6B. Our findings suggest that compound LOF and ultrarare missense variants may be contribute to the underlying variability expressivity associated with this disorder. In conclusion, our findings support that the clinical severity could be related with the predicted functional severity of the variations in OTUD6B. However, additional functional studies are required. Copyright © 2022 Elsevier Masson SAS. All rights reserved.


    Sultan Cingöz, Didem Soydemir, Tülay Öncü Öner, Ezgi Karaca, Burcu Özden, Semra Hız Kurul, Erhan Bayram, University of Washington Center for Mendelian Genomics, Bradley P Coe, Deborah A Nickerson, Evan E Eichler. Novel biallelic variants affecting the OTU domain of the gene OTUD6B associate with severe intellectual disability syndrome and molecular dynamics simulations. European journal of medical genetics. 2022 Jun;65(6):104497

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    PMID: 35430327

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