Abstracts, Posters, Oral Presentations

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

Data sharing to improve concordance in variant interpretation across laboratories: Results from the Canadian Open Genetics Repository


Accurate variant interpretation is essential for the benefits of clinical genetic testing to be realized. In variant interpretation, multiple lines of evidence are considered to evaluate a
variant’s pathogenicity. Despite guidelines from the American College of Medical Genetics and Genomics (ACMG) and the Association of Molecular Pathology (AMP), discordant
variant classifications exist between laboratories. Data sharing may improve concordance in variant interpretation. The Canadian Open Genetics Repository (COGR) is a collaborative
effort for sharing and reinterpreting variants reported by diagnostics laboratories, using an online platform. Previously, we found that COGR was effective at improving concordance
in BRCA1 and BRCA2 variant interpretation across 13 laboratories. We now expand our efforts to all genes tested at the participating laboratories.

Read More

Genotype–phenotype associations in a large PRPH2‐related retinopathy cohort


Molecular variant interpretation lacks disease gene‐specific cohorts for determining variant enrichment in disease versus healthy populations. To address the molecular etiology of retinal degeneration, specifically the PRPH2‐related retinopathies, we reviewed genotype and phenotype information obtained from 187 eyeGENE® participants from 161 families. Clinical details were provided by referring clinicians participating in the eyeGENE® Network. The cohort was sequenced for variants in PRPH2 . Variant complementary DNA clusters and cohort frequency were compared to variants in public databases to help us to determine pathogenicity by current American College of Medical Genetics and Genomics/Association for Molecular Pathology interpretation criteria. The most frequent variant was c.828+3A>T, which affected 28 families (17.4%), and 25 of 79 (31.64%) variants were novel. The majority of missense variants clustered in the D2 intracellular loop of the peripherin‐2 protein, constituting a hotspot. Disease enrichment was noted for 23 (29.1%) of the variants. Hotspot and disease‐enrichment evidence modified variant classification for 16.5% of variants. The missense allele p.Arg172Trp was associated with a younger age of onset. To the best of our knowledge, this is the largest patient cohort review of PRPH2‐related retinopathy. Large disease gene‐specific cohorts permit gene modeling for hotspot and disease‐enrichment analysis, providing novel variant classification evidence, including for novel missense variants.

Read More

Deficiency of MFSD7c results in microcephaly-associated vasculopathy in Fowler syndrome

Several missense mutations in the orphan transporter FLVCR2 have been reported in Fowler syndrome. Affected subjects exhibit signs of severe neurological defects. We identified the mouse ortholog Mfsd7c as a gene expressed in the blood-brain barrier. Here, we report the characterizations of Mfsd7c-KO mice and compare these characterizations to phenotypic findings in humans with biallelic FLVCR2 mutations. Global KO of Mfsd7c in mice resulted in late-gestation lethality, likely due to CNS phenotypes. We found that the angiogenic growth of CNS blood vessels in the brain of Mfsd7c-KO embryos was inhibited in cortical ventricular zones and ganglionic eminences. Vascular tips were dilated and fused, resulting in glomeruloid vessels. Nonetheless, CNS blood vessels were intact, without hemorrhage. Both embryos and humans with biallelic FLVCR2 mutations exhibited reduced cerebral cortical layers, enlargement of the cerebral ventricles, and microcephaly. Transcriptomic analysis of Mfsd7cK-KO embryonic brains revealed upregulation of genes involved in glycolysis and angiogenesis. The Mfsd7c-KO brain exhibited hypoxia and neuronal cell death. Our results indicate that MFSD7c is required for the normal growth of CNS blood vessels and that ablation of this gene results in microcephaly-associated vasculopathy in mice and humans.

Read More

ATAV - a comprehensive platform for population-scale genomic analyses

Summary We present ATAV, an analysis platform for large-scale whole-exome and whole-genome sequencing projects. ATAV stores variant and coverage data for all samples in a centralized database, which is then efficiently queried by ATAV to support diagnostic analyses for trios and singletons, as well as rare-variant collapsing analyses for finding disease associations in complex diseases. Runtime logs ensure full reproducibility and the modularized ATAV framework makes it extensible to continuous development of new functions. In recent years ATAV has not only been helpful for identifying disease-causing variants for a range of diseases, but has also enabled the discovery of novel genes by rare-variant collapsing on datasets containing more than 20,000 samples. Analyses to date have been performed on more than 110,000 sequenced individuals demonstrating that the framework is robust to large-scale studies.

Read More

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.

Read More

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.

Read More

Establishing the role of PLVAP in protein-losing enteropathy

A homozygous missense variant leads to an attenuated phenotype

Rambam medical center report on familial whole-exome sequencing analysis, performed using Genoox software, to reveal a homozygous mutation in the PLVAP gene (c.101T>C). This variant was found to be co-segregated with a severe congenital protein-losing enteropathy (PLE).

Read More

Trio Clinical Exome Sequencing in a Patient With Multicentric Carpotarsal Osteolysis Syndrome

Rare disease discovery - First Case Report in the Balkans

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).

Read More

Prenatal and postnatal presentation of PRMT7 related syndrome

Expanding the phenotypic manifestations

Wolfson Medical Center report on familial whole-exome sequencing analysis, performed using Genoox software, to reveal a novel homozygous mutation in the PRMT7 gene (c.1074_1075delAG). This variant was found to co-segregated in a family with intrauterine growth restriction (IUGR)- mainly the long bones, global developmental delay, dysmorphic features and other postnatal manifestations. 

Read More

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.

Read More

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 frameshift 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.

Read More

STAT1 gain‐of‐function and chronic demodicosis

Hadassah medical center report on familial whole-exome sequencing analysis, which revealed a heterozygous gain‐of‐function mutations in the STAT1 gene (c.821G>A). This variant was found to co-segregated in a family with chronic demodicosis.

Read More

A novel TUFM homozygous variant in a child with mitochondrial cardiomyopathy expands the phenotype of combined oxidative phosphorylation deficiency 4

A novel homozygous missense variant in TUFM (c.344A>C) encoding mtDNA translation elongating factor Tu (EFTu) was identified by using Genoox software family analysis in trio-based Whole-exome sequencing. 

The patient presented here expands the phenotypic features of TUFM-related disease, exhibiting lactic acidosis and dilated cardiomyopathy without progressive encephalopathy.

Read More

A Unique Presentation of Infantile-Onset Colitis and Eosinophilic Disease without Recurrent Infections Resulting from a Novel Homozygous CARMIL2 Variant

a boy with severe infantile-onset colitis and eosinophilic gastrointestinal disease and no evidence of recurrent or severe infections went through a Trio whole-exome analysis via Genoox software revealing a homozygous variant in the capping protein regulator and myosin 1 linker 2 (CARMIL2) gene (c.1590C>A) which co-segregated with the disease in the nuclear family. This case extend the role of CARMIL2 gene to be responsible also to early-onset inflammatory and eosinophilic gastrointestinal disorders, even when signs of immunodeficiency are not observed.

Read More

Identification of a novel PCNT founder pathogenic variant in the Israeli Druze population

In this paper Rambam Medical center describes the identification of a novel founder pathogenic variant in PCNT gene (c.3465-1G > A) observed in carriers from multiple Druze villages in Northern Israel. 

Read More

Infantile onset progressive cerebellar atrophy and anterior horn cell Degeneration-A novel phenotype associated with mutations in the PLA2G6 gene

In this paper, Wolfson Medical Center reports on a homozygous mutation in the PLA2G6 gene detected in two siblings from a consanguineous Moslem Arabic family with a unique combination of progressive cerebellar atrophy and a SMA-like anterior horn cell degeneration.  PLA2G6 was thus suggested to affect late-onset Pontocerebellar hypoplasia (PCH). 

Read More

Homozygosity for CHEK2 p.Gly167Arg leads to a unique cancer syndrome with multiple complex chromosomal translocations in peripheral blood karyotype

Two patients presented with multiple chromosomal translocations, with an early-onset multiorgan tumourogenesis and and early-onset acute myeloid leukaemia, were sequenced by the Rambam Medical Center. By applying the Genoox prioritization engine, the same homozygous mutation in CHEK2 (c.499G>A)  was identified, revealing its role as a cancer predisposition alteration.   

Read More

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.

Read More

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.

Read More

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.

Read More

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.

Read More

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

Read More

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%).

Read More

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.

Read More

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.

Read More
Put Genoox to work for you


Find out more about our advanced tools and services: