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Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency.

ABSTRACT: Coagulation factor X (FX), often termed as Stuart-Prower factor, is a plasma glycoprotein composed of the γ-carboxyglutamic acid (GLA) domain, two epidermal growth factor domains (EGF-1 and EGF-2), and the serine protease (SP) domain. FX plays a pivotal role in the coagulation cascade, activating thrombin to promote platelet plug formation and prevent excess blood loss. Genetic variants in FX disrupt coagulation and lead to FX or Stuart-Prower factor deficiency. To better understand the relationship between FX deficiency and disease severity, an interactive FX variant database has been set up at https://www.factorx-db.org , based on earlier web sites for the factor-XI and -IX coagulation proteins. To date (April 2021), we report 427 case reports on FX deficiency corresponding to 180 distinct F10 genetic variants. Of these, 149 are point variants (of which 128 are missense), 22 are deletions, 3 are insertions, and 6 are polymorphisms. FX variants are phenotypically classified as being type I or II. Type-I variants involve the simultaneous reduction of FX coagulant activity (FX:C) and FX antigen levels (FX:Ag), whereas type-II variants involve a reduction in FX:C with normal FX:Ag plasma levels. Both types of variants were distributed throughout the FXa protein structure. Analyses based on residue surface accessibilities showed the most damaging variants to occur at residues with low accessibilities. The interactive FX web database provides a novel easy-to-use resource for clinicians and scientists to improve the understanding of FX deficiency. Guidelines are provided for clinicians who wish to use the database for diagnostic purposes.

SUBMITTER: Harris VA

PROVIDER: S-EPMC8763577 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Focal malformations of cortical development including focal cortical dysplasia, hemimegalencephaly and megalencephaly, are a spectrum of neurodevelopmental disorders associated with brain overgrowth, cellular and architectural dysplasia, intractable epilepsy, autism and intellectual disability. Importantly, focal cortical dysplasia is the most common cause of focal intractable paediatric epilepsy. Gain and loss of function variants in the PI3K-AKT-MTOR pathway have been identified in this spectrum, with variable levels of mosaicism and tissue distribution. In this study, we performed deep molecular profiling of common PI3K-AKT-MTOR pathway variants in surgically resected tissues using droplet digital polymerase chain reaction (ddPCR), combined with analysis of key phenotype data. A total of 159 samples, including 124 brain tissue samples, were collected from 58 children with focal malformations of cortical development. We designed an ultra-sensitive and highly targeted molecular diagnostic panel using ddPCR for six mutational hotspots in three PI3K-AKT-MTOR pathway genes, namely PIK3CA (p.E542K, p.E545K, p.H1047R), AKT3 (p.E17K) and MTOR (p.S2215F, p.S2215Y). We quantified the level of mosaicism across all samples and correlated genotypes with key clinical, neuroimaging and histopathological data. Pathogenic variants were identified in 17 individuals, with an overall molecular solve rate of 29.31%. Variant allele fractions ranged from 0.14 to 22.67% across all mutation-positive samples. Our data show that pathogenic MTOR variants are mostly associated with focal cortical dysplasia, whereas pathogenic PIK3CA variants are more frequent in hemimegalencephaly. Further, the presence of one of these hotspot mutations correlated with earlier onset of epilepsy. However, levels of mosaicism did not correlate with the severity of the cortical malformation by neuroimaging or histopathology. Importantly, we could not identify these mutational hotspots in other types of surgically resected epileptic lesions (e.g. polymicrogyria or mesial temporal sclerosis) suggesting that PI3K-AKT-MTOR mutations are specifically causal in the focal cortical dysplasia-hemimegalencephaly spectrum. Finally, our data suggest that ultra-sensitive molecular profiling of the most common PI3K-AKT-MTOR mutations by targeted sequencing droplet digital polymerase chain reaction is an effective molecular approach for these disorders with a good diagnostic yield when paired with neuroimaging and histopathology.

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Analysis of 180 Genetic Variants in a New Interactive FX Variant Database Reveals Novel Insights into FX Deficiency.

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