Large multicenter study identifies 34 new genetic diseases

Most rare diseases have a genetic cause. The underlying genetic alteration can be detected increasingly easily, for example by exome sequencing (ES), which enables molecular genetic diagnosis. ES involves examining all sections of our genetic material (DNA) that code for proteins. In a multicenter study conducted across Germany, ES data were collected from 1,577 patients and systematically evaluated.

A total of 499 patients could be diagnosed, 34 of whom had new, previously unknown genetic diseases. The study thus makes a significant contribution to the initial description of new diseases. In addition, software based on the use of artificial intelligence (AI) was used for the first time on a large scale to support clinical diagnosis.

The AI ​​system “GestaltMatcher” can help in the assessment of facial features for the classification of congenital genetic syndromes. The results of the study, which involved 16 university sites, were published in Genetics of nature.

Ultra-rare diseases require multidisciplinary clinical expertise and comprehensive genetic diagnosis for optimal care. The three-year TRANSLATE NAMSE innovation fund project began at the end of 2017 with the aim of improving the care of those affected by modern diagnostic concepts.

Researchers from 16 university hospitals analyzed ES data from 1,577 patients, including 1,309 children, who presented to rare disease centers as part of TRANSLATE NAMSE. The aim of the project was to find the cause of the disease in as many patients as possible using innovative examination methods.

The genetic cause of this rare disease was identified in 499 patients, including 425 children. In total, the researchers found changes in 370 different genes.

“We are particularly proud of the discovery of 34 new molecular diseases, which is an excellent example of knowledge-generating patient care in university hospitals,” says Dr. Theresa Brunet, one of the lead authors from the Institute of Human Genetics at the Clinic rechts der Isar at the Technical University of Munich.

What happens next with the unsolved cases?

“As part of the model project Genome Sequencing, or MVGenomSeq for short, we will examine affected patients for whom we have not yet been able to find a diagnosis,” explains Dr. Tobias Haack, Deputy Director of the Institute of Medical Genetics and Applied Genomics at the University Hospital Tübingen.

The MVGenomSeq project builds on the success of the TRANSLATE NAMSE project and enables the analysis of clinical genomes in university hospitals throughout Germany. Unsolved cases can also be investigated in follow-up studies using new analysis methods, such as long-read sequencing, which allows the analysis of much longer DNA fragments.

“Long-read sequencing allows us to find genetic changes that are difficult to detect and we assume that we will be able to make further diagnoses using this method,” says Dr. Nadja Ehmke, head of genome diagnostics at the Institute of Medical and Human Genetics at Charité and one of the last authors.

As part of the TRANSLATE NAMSE project, standardized procedures for extended genetic diagnosis for suspected rare diseases were also established in participating rare disease centers, based on interdisciplinary case conferences. These procedures were integrated into standard care after the project was completed.

“Interdisciplinary case conferences play an important role for those affected. They enable a comprehensive clinical characterization, which is relevant for the phenotypic evaluation of genetic data. In addition, detected variants can be discussed in an interdisciplinary context,” says Dr. Magdalena Danyel, one of the first authors, who works as a specialist at the Institute of Medical Genetics and Human Genetics and a member of the clinician-scientist program of the Berlin Institute of Health (BIH) at Charité-Universitätsmedizin.

Rare genetic diseases can sometimes be recognized by the face

The researchers also studied whether the complementary use of machine learning and artificial intelligence (AI) tools improves the effectiveness and efficiency of diagnosis.

To this end, the “GestaltMatcher” software developed by researchers from Bonn, which uses computer-aided facial analysis to support the person using it in the diagnosis of rare diseases, was tested for the first time on a large scale.

The study used sequence and image data from 224 people who also consented to computer-assisted analysis of their facial images, and the AI-assisted technology was shown to offer a clinical benefit.

GestaltMatcher AI can recognize facial abnormalities and attribute them to specific diseases. An important question when evaluating genetic data is: does the phenotype match the genotype? AI can help here.

“GestaltMatcher is like an expert opinion that we can provide to any healthcare professional in seconds. Early diagnosis is essential for people affected by rare diseases and their families. The use of the software by pediatricians could already be useful in case of abnormalities during U7 screening at 21-24 months or U7a at 34-36 months,” says corresponding author Professor Peter Krawitz, Director of the Institute for Genomic Statistics and Bioinformatics (IGSB) at the University Hospital Bonn (UKB), where the GestaltMatcher AI is being developed.

Professor Krawitz is also a member of the ImmunoSensation2 Cluster of Excellence and the Transdisciplinary Research Areas (TRA) “Modeling” and “Life and Health” at the University of Bonn. The software and app can be made available to all physicians through the non-profit organization Arbeitsgemeinschaft für Gen-Diagnostik eV (AGD).