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EnGenome Eyes Return to US Market with Rare Disease Diagnostics Software


CHICAGO – Three years after completing a pivot from a consulting firm to a software company, Italian bioinformatics startup EnGenome is eyeing a return to the US market. The company is also preparing to expand the capabilities of its software into digenic rare disease diagnostics.

Pavia, Italy-based EnGenome has also begun marketing its eVai variant interpretation and annotation software in the US. The firm has not had any customers stateside since it completed a consultancy project with the Medical College of Wisconsin more than three years ago.

EnGenome initially provided bioinformatics consulting services but pivoted to software only when it introduced eVai in 2019. eVai, which received a CE-IVD mark that same year, is a software-as-a-service platform for detecting pathogenetic variants and suggesting potential diagnoses.

Currently, most of EnGenome's customers are major hospitals in Italy, though the company has users in Spain, Greece, Portugal, and South Africa, according to CEO and Cofounder Ettore Rizzo.

EnGenome gained some recognition in America earlier this year when eVai was named "best-performing predictor" in CAGI6, the most recent challenge of the Critical Assessment of Genome Interpretation (CAGI) program, organized by the University of California, Berkeley and funded by the US National Institutes of Health.

Participants in the CAGI6 challenge, which wrapped up in May, were given whole-genome sequence data and phenotypes of a small cohort of 30 families as part of the Broad Institute-led Rare Genomes Project and were asked to demonstrate how their technology could uncover causative variants in children with rare diseases.

The CAGI6 challenge judged competitors on their technology's assessment of pathogenicity of variants in patients that already had diagnoses as well as the ability to solve new cases. During the challenge, EnGenome was able to diagnose two previously unsolved cases, increasing the diagnostic yield by 13 percent.

The company said that it was the only competitor to uncover a combination of a coding and a deep-intronic variant on the ASNS gene to produce a diagnosis of the neurodevelopmental disorder asparagine synthetase deficiency in a newborn. EnGenome also found a variant of TCF4 to diagnose Pitt-Hopkins syndrome, a condition on the autism spectrum.

Rizzo said that CAGI6 organizers at UC-Berkeley will detail the work in a forthcoming paper.

Meantime, EnGenome is hoping to further improve diagnosis of rare hereditary diseases by expanding eVai into digenic analysis. "Our hypothesis is that [by] going beyond the 'one gene-one disease' paradigm that's the foundation of how genetic tests are interpreted today, we will be able to increase diagnostic yield," Rizzo said. "We want to explore the pathogenicity of a variant combination," Rizzo said.

The current version of eVai, the one that was named best performer at the CAGI6 challenge, evaluates a single variant at a time. 

EnGenome pulls from more than 30 public omics databases. Based on that information, the company has built its own knowledgebase of confirmed variants to feed its machine learning algorithms, with the aim of improving the accuracy of its analysis.

Following American College of Medical Genetics and Genomics and Association for Molecular Pathology guidelines for variant interpretation with its machine learning, eVai classifies and ranks variants for pathogenicity, then suggests potential diagnoses.

EnGenome, which emerged from University of Pavia in 2016, is funding development of this digenic capability with a €1.7 million ($2 million at the time) grant it won last October through the European Innovation Council's business accelerator program. Though the European Innovation Council made the award nearly a year ago, the work officially started in May, according to Rizzo.

The company has not received any venture capital investments to date, but has raised an undisclosed amount of money from angel investors as well as the grant. However, Rizzo said that growth has mostly been "organic" since the beginning, with operations largely funded by revenue.

Rizzo did not rule out the possibility of raising a seed round in the future to accelerate technology development or expand sales and marketing efforts. "We keep our eyes open with regards to venture capital funding," Rizzo said. 

Rizzo and the other two founders, Chief Technology Officer Ivan Limongelli and CSO Susanna Zucca met as Ph.D. students at the University of Pavia in 2010, where they processed next-generation sequencing data for cancer and hereditary diseases.

By 2015, they had decided to create a company to improve variant interpretation. They incorporated EnGenome a year later and launched eVai in 2019 after more than two years of software development.

Rizzo said that EnGenome made a conscious decision in its early days to target rare disease, based on feedback from some of its first consultancy customers. "We saw that there was a real need from the genetic testing laboratory in the interpretation of hereditary diseases because of the complexity of the variant interpretation process," he said.

EnGenome currently employs about 15 people, including bioinformaticians, software developers, biotechnologists, and geneticists. The company also has scientific advisers affiliated with the University of Pavia and Mount Sinai Health System in New York.

In 2020, EnGenome integrated Genomenon's Mastermind Genomic Search Engine into eVai. Since then, users have been able to preview the number of published articles related to their search in the eVai platform and easily link out to view the evidence in Mastermind.