Abstracts, Posters, Oral Presentations

Find out how our clients made new discoveries using the Genoox platform

Using Artificial Intelligence for Detection of Hotspot Regions

ACMG/AMP PM1 Criterion

Genoox demonstrated AI-based algorithms can aid in the detection of exonic and domain hotspot locations in genes. Due to the lack of gold standard databases for applying PM1 rule, An AI-based hotspot detection is highly desirable. Our results show that the identification of the hotspot was consistent with the final classification of a variant by the Expert Panels. As such, it can be valuable tool for making future investigations of gene-based variant classification.

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Implementation of Gene-specific ClinGen Variant Classification Recommendations using Artificial Intelligence

Frequency Thresholds

The 2015 ACMG/AMP sequence variant interpretation guidelines provided a framework for classifying variants based on several benign and pathogenic evidence criteria. Recently, ClinGen has introduced several expert gene/disease panels to establish more specific classification recommendations.

We hypothesized that artificial intelligence (AI)-based algorithms that are focused on implementation of gene-specific recommendations may aid in the process of variant curation.

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Reinterpretation of Sequence Variants Using Artificial Intelligence

Evaluating Genoox AI Engine as a Tool For Performing Variant Reinterpretation

These benchmarking results demonstrate the aiVCE’s ability to classify variants at a high rate of concordance with expert curation. The high level of agreement with challenging variants, such as those in the Discordant Dataset, makes the aiVCE ideal to expedite reinterpretation of variants accumulated over time. The aiVCE can be designed to monitor and alert the lab of variants with significant classification changes at predetermined time intervals.

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Using Artificial Intelligence for Implementing New Recommendations of the PVS1 Loss of Function Criterion

The aiVCE algorithm demonstrated excellent concordance with the ClinGen SVI Workgroup results. Further, the 5 variants demonstrating discordant classification strength illustrate an advantage of using an AI-based tool, as the identification of these variants as P were in agreement with the new ClinGen SVI Workgroup recommendations. Implementation of new recommendations for more accurate interpretation of null variants involves demanding and complex bioinformatics work, and AI-based solutions can enhance current interpretation guidelines.

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A Novel Approach for Structural Variant Calling

Combining Data from Whole Genome Next-generation Sequencing and Optical Mapping

A novel joint pipeline integrating NGS raw data with optical mapping provided SV calls characterized by precise breakpoint positions and low false-positive rates, suggesting the advanced graph structure could have considerable utility in clinical practice.

American Society of Human Genetics 2018 Annual Meeting
October 16–20, 2018 – San Diego, CA

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Genoox AI engine helps discovering metabolic stroke in a patient with bi-allelic OPA1 mutations

OPA1 related disorders include: classic autosomal dominant optic atrophy syndrome (ADOA), ADOA plus syndrome and a bi- allelic OPA1 complex neurological disorder. We describe metabolic stroke in a patient with bi-allelic OPA1 mutations. A twelve- year old girl presented with a complex neurological disorder that includes: early onset optic atrophy at one year of age, progressive gait ataxia, dysarthria, tremor and learning impairment. A metabolic stroke occurred at the age of 12 years. The patient was found to harbor a de novo heterozygous frame shift mutation c.1963_1964dupAT; p.Lys656fs (NM_015560.2) and a missense mutation c.1146A > G; Ile382Met (NM_015560.2) inherited from her mother. The mother, aunt, and grandmother are heterozygous for the Ile382Met mutation and are asymptomatic. The co-occurrence of bi-allelic mutations can explain the severity and the early onset of her disease. This case adds to a growing number of patients recently discovered with bi-allelic OPA1 mutations presenting with a complex and early onset neurological disorder resembling Behr syndrome. To the best of our knowledge metabolic stroke has not been described before as an OPA1 related manifestation. It is important to be aware of this clinical feature for a prompt diagnosis and consideration of available treatment.

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Benchmarking an Automated Variant Classification Engine (aVCE) Algorithm Using ClinVar

Results of a Time-Capsule Experiment

The Genoox aVCE was ‘trained’ on the ClinVar database (version 30-06-17). Variants with Reference/Submission ClinVar (RCV/SCV) creation dates before and after 01-07-16 were marked as ‘Train’ and ‘Test,’ respectively.

When compared against ClinVar submissions from clinical laboratories and high-certainty entries, the proprietary aVCE classified clinically ‘actionable’ (P/LP) and ‘non-actionable’ (VUS/LB/B) variants with very high sensitivity (99.29%, 1262/1271) and specificity (100%).

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Rare Disease Diagnostics

Improving Diagnosis Yield With Reanalysis and AI for Rare Disease - A Single-center Experience and Lessons Learnt

An accurate molecular diagnosis can set the stage for improved patient care and provides an opportunity to study disease mechanisms, which may lead to development of tailored treatments. Data from our genetic research program demonstrate high diagnostic and novel disease-associated or causative gene discovery rates. This is likely related to the unique genetic architecture of the population in Northern Israel as well as to our strategy for case selection and the close collaboration between analysts, geneticists, and clinicians, all working in the same hospital.

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Rare disease discovery

First Case Report in the Balkans: Trio Clinical Exome Sequencing in a Patient With Multicentric Carpotarsal Osteolysis Syndrome

Testing the proband and her parents led to the identification of a de novo mutation c.188C>T (p.Pro63Leu) in the MAFB gene, which is known to cause multicentric carpotarsal osteolysis syndrome (MCTO).

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NGS validation

Comparing exome performance and Sanger-sequencing in the clinical setting

Clinical uses of Next Generation Sequencing (NGS) are continually expanding as the cost of the technology falls while clinical utility increases at a rapid rate., What was once a “last resort” technique for exceptional cases in which a molecular diagnosis could not be achieved by standards means has now become a routine test allowing physicians to translate genomic information into clinically actionable decisions.

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Rare disease discovery

Genoox reveals loss of Glycine Transporter 1 Causes a Subtype of Glycine Encephalopathy with Arthrogryposis and Mildly Elevated Cerebrospinal Fluid Glycine

The Genoox sophisticated interpretation engine provides both automatic annotation and classification of variants, as well as advanced sample comparison and the ability to analyze families and examine different inheritance models, providing rapid clinical answers in minutes rather than hours or days.

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Rare disease discovery

Genoox reveals loss of CD55 in eculizumab-responsive protein-losing enteropathy

Rambam medical center leverages the Genoox platform to reveal how a homozygous frameshift variant in CD55 segregates with protein-losing enteropathy associated with hypercoagulability, using WES. These findings influences the treatment strategy were the patients were treated with the terminal complement inhibitor eculizumab, which has proven therapeutic benefits in other disorders of complement dysregulation, such as CD59 deficiency.

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Loss of Protocadherin‐12 Leads to Diencephalic‐Mesencephalic Junction Dysplasia Syndrome

Eight families with DMJD were studied by whole-exome or targeted sequencing, with detailed clinical and radiological characterization. Patient-derived induced pluripotent stem cells were derived into neural precursor and endothelial cells to study gene expression.

All patients showed biallelic mutations in the nonclustered protocadherin-12 (PCDH12) gene. The characteris- tic clinical presentation included progressive microcephaly, craniofacial dysmorphism, psychomotor disability, epilepsy, and axial hypotonia with variable appendicular spasticity. Brain imaging showed brainstem malformations and with fre- quent thinned corpus callosum with punctate brain calcifications, reflecting expression of PCDH12 in neural and endo- thelial cells. These cells showed lack of PCDH12 expression and impaired neurite outgrowth.

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