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Simons C.,University of Queensland | Simons C.,Garvan Institute of Medical Research | Simons C.,Acibadem University | Simons C.,University of Liège | And 4 more authors.
Nature genetics | Year: 2015

Temple-Baraitser syndrome (TBS) is a multisystem developmental disorder characterized by intellectual disability, epilepsy, and hypoplasia or aplasia of the nails of the thumb and great toe. Here we report damaging de novo mutations in KCNH1 (encoding a protein called ether à go-go, EAG1 or KV10.1), a voltage-gated potassium channel that is predominantly expressed in the central nervous system (CNS), in six individuals with TBS. Characterization of the mutant channels in both Xenopus laevis oocytes and human HEK293T cells showed a decreased threshold of activation and delayed deactivation, demonstrating that TBS-associated KCNH1 mutations lead to deleterious gain of function. Consistent with this result, we find that two mothers of children with TBS, who have epilepsy but are otherwise healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with recent reports, this finding demonstrates that the etiology of many unresolved CNS disorders, including epilepsies, might be explained by pathogenic mosaic mutations.


Patent
Real Time Genomics | Date: 2013-08-30

Methods of calling genomic sequence values in complex calling regions are disclosed. Following a preliminary sequence alignment a complex calling region may be identified where no sequence values satisfy preliminary alignment criteria. Potential hypotheses may be formulated for the complex calling region and the probability of each hypothesis representing a correct alignment may be calculated by evaluating the probability of each hypothesis being correct for the reads and the probability of each hypothesis occurring. The hypothesis best satisfying hypothesis selection criteria may be selected. The method may include an evaluation of possible indels in the complex calling region.


Methods and an apparatus according to the present invention, can be used in capture/enrichment, gene expression profiling and targeted sequencing. Provided are methods for improving accuracy and stringency of microarrays and/or other genomic analysis methods relying on nucleic acid hybridization and melting curve analysis by controlling surface chemistry. This method comprises producing a positively charged surface or surface coating, on the surface of microarray slides or other types of surfaces similarly purposed, such as micro beads, which enhances melting curve analysis to the point of allowing detection or differentiation of small changes in sequences between nucleic acid binding partners. Also provided is an improved microarray reader machine, to collect melting curve data on microarray slides. The accuracy or resolution of melting curve analysis was to be sufficient to distinguish between the melting of perfect matched dsDNA and dsDNA with the smallest possible change in sequence, a one base pair mismatch.


A computer implemented method for characterizing one or more sequences by generating index values representing portions of the sequences and finding characterizing index values based on a comparison of the index values. The index values may be obtained by applying one or more mask over each sequence. The modified masks may have associated weightings and index values obtained using modified masks may be retained in the index only if the weightings are above a threshold value. Characterising index values may also be assessed for for their degree of uniqueness. Characterizing indexes may be used for predicting correlation between a sample sequence and one or more reference sequences. Biological monitoring systems utilising the characterizing index values are also disclosed. A biological indicator may be generatgenerated using one or more characterizing index values obtained by the above method and be used to produce an indicator that undergoes a property change in the presence of the one or more sequence.


Patent
Real Time Genomics | Date: 2013-06-24

Methods and systems for evaluating genomic sequences are described. The methods include approaches for evaluating the prevalence of genomes in a sample based on the prevalence of segments in the sample, and may additionally rely on the prevalence of segments in reference genomes and an estimated genome population distribution of the sample.


Patent
Real Time Genomics | Date: 2013-08-20

Methods and systems for simultaneously evaluating genomic sequences across multiple population members, and methods and systems for simultaneously calling normal and cancerous genomic sequences from a mixed sample containing normal and cancerous material are disclosed. This may be achieved by evaluating the probability of one or more hypothesis being correct for a plurality of population members based on genomic sequence information for the population. For related family members, Mendelian inheritance may be integrated into the method. For populations, information from members under evaluation may be used to refine priors to more accurately call population members. Copy number variation and de novo mutations may also be accommodated in the methods. Specific systems for implementing the methods are also disclosed.


Patent
Real Time Genomics | Date: 2013-08-20

Methods and systems for simultaneously evaluating biological sequences across multiple population members, and methods and systems for simultaneously calling normal and cancerous biological sequences from a mixed sample containing normal and cancerous material are disclosed. This may be achieved by evaluating the probability of one or more hypothesis being correct for a plurality of population members based on biological sequence information for the population. For related family members, Mendelian inheritance may be integrated into the method. For populations, information from members under evaluation may be used to refine priors to more accurately call population members. Copy number variation, de novo mutations, and phenotypic traits and their genetic explanations may also be accommodated in the methods. Specific systems for implementing the methods are also disclosed.


A computer implemented method for characterizing one or more sequences by generating index values representing portions of the sequences and finding characterizing index values based on a comparison of the index values. The index values may be obtained by applying one or more mask over each sequence. The modified masks may have associated weightings and index values obtained using modified masks may be retained in the index only if the weightings are above a threshold value. Characterising index values may also be assessed for for their degree of uniqueness. Characterizing indexes may be used for predicting correlation between a sample sequence and one or more reference sequences. Biological monitoring systems utilising the characterizing index values are also disclosed. A biological indicator may be generatgenerated using one or more characterizing index values obtained by the above method and be used to produce an indicator that undergoes a property change in the presence of the one or more sequence.


Trademark
Real Time Genomics | Date: 2012-07-10

Computer software, namely, executable computer software for analysis and management of genetic sequence data within variant detection, metagenomics, transcriptomics and molecular diagnostics applications in the fields of personalized medicine, healthcare, agbio, bio-fuels and environmental security.


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