Genetic diagnostics of ultra-rare diseases (2024)

Ultra-rare diseases require both multidisciplinary clinical expertise and comprehensive genetic diagnostics 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 means of modern diagnostic concepts. Researchers from 16 university hospitals analyzed the ES data of 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. A genetic cause of the rare disease was identified in 499 patients, 425 of whom were 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 a great example of knowledge-generating patient care at university hospitals," says Dr. Theresa Brunet, one of the lead authors from the Institute of Human Genetics at the Klinikum rechts der Isar of the Technical University of Munich.

What happens next with the unsolved cases?

"We will examine the affected patients for whom we have not yet been able to find a diagnosis as part of the model project Genome Sequencing, or MVGenomSeq for short," says Dr. Tobias Haack, Deputy Director of the Institute of Medical Genetics and Applied Genomics at the University Hospital of Tübingen. The MVGenomSeq builds on the success of the TRANSLATE NAMSE project and enables the analysis of clinical genomes at university hospitals throughout Germany. Unsolved cases can also be investigated in follow-up studies using new examination methods, such as long-read sequencing, which allows much longer DNA fragments to be analyzed. "Long-read sequencing enables 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 Charité's Institute of Medical Genetics and Human Genetics and one of the last authors.

As part of the TRANSLATE NAMSE project, standardized procedures for extended genetic diagnostics for suspected rare diseases were also established at the participating rare disease centers, based on interdisciplinary case conferences. These were incorporated into standard care after the project was completed. "The interdisciplinary case conferences play an important role for those affected. This enables a comprehensive clinical characterization, which is relevant for the phenotype-based evaluation of the genetic data. In addition, the 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 fellow 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 investigated whether the supplementary use of machine learning and artificial intelligence (AI) tools improves diagnostic effectiveness and efficiency. To this end, the "GestaltMatcher" software developed by researchers in Bonn, which uses computer-assisted facial analysis to support the person using it in the diagnosis of rare diseases, was tested on a broad scale for the first time. The study used the sequence and image data of 224 people who had also consented to the computer-assisted analysis of their facial images, and it was shown that the AI-supported technology provides a clinical benefit.

The GestaltMatcher AI can recognize abnormalities in the face and assign them to specific diseases. An important question when assessing genetic data is: Does the phenotype match the genotype? The AI can provide support here. "GestaltMatcher is like an expert opinion that we can provide to any medical professional in a matter of seconds. Early diagnosis is essential for those affected by rare diseases and their families. Supportive use of the software by pediatricians could already be useful in the case of abnormalities during the U7 screening at 21 to 24 months or U7a at 34 to 36 months," says corresponding author Prof. 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. Prof. Krawitz is also a member of the Cluster of Excellence ImmunoSensation2 and in the Transdisciplinary Research Areas (TRA) "Modeling" and "Life & Health" at the University of Bonn. The software and app can be made available to all doctors through the non-profit organization Arbeitsgemeinschaft für Gen-Diagnostik e.V. (AGD).

Genetic diagnostics of ultra-rare diseases (2024)

FAQs

Are 80% of all rare diseases genetic? ›

Around 80% of rare diseases are of genetic origin. 70% of rare diseases start in childhood.

How rare is ultra-rare disease? ›

An Ultra-rare disease is a condition that affects fewer than 1 in 50,000 people. This means that in the U.S., for any ultra-rare disease, less than 7000 people live with that condition. Some of these diseases are so rare that only a few people in the world have it.

Are 72% of rare diseases genetic? ›

Three hundred million people worldwide live with a rare disease. One in 10 Americans has a rare disease, and about half of them are children. Of the more than 6,800 rare diseases that have been identified, 72% are genetic. Seventy percent of rare genetic disorders start in childhood.

How do you test for rare genetic diseases? ›

Whole-genome sequencing is the most comprehensive method for rare disease testing. It examines the entire genome and has the capability to assess variants in both coding and noncoding regions of the genome.

Is 1 in 2000 rare? ›

The term low prevalence is later defined as generally meaning fewer than 1 in 2,000 people. Diseases that are statistically rare, but not also life-threatening, chronically debilitating, or inadequately treated, are excluded from their definition.

What is the rarest genetic in the world? ›

The Rarest of the Rare
  • Hutchinson-Gilford Progeria Syndrome (HGPS) Frequency: Occurs in 1 in 4 million newborns worldwide. ...
  • Alkaptonuria. Frequency: Occurs in 1 in 250,000 -1,000,000 live births. ...
  • Ribose-5-phosphate isomerase deficiency. ...
  • Ogden syndrome. ...
  • KAT6A syndrome.
Feb 23, 2021

What is the rarest disease in the universe? ›

This is considered to be the rarest disease in the world. Ribose-5-Phosphate Isomerase (RPI), is a crucial enzyme in a metabolic process in the human body. This condition can cause muscle stiffness, seizures, and reduction of white matter in the brain.

Which drug is used to treat ultra rare medical conditions? ›

An orphan drug is a drug for a rare disease or condition. Some rare disease treatments have been “orphaned” or discontinued because there was not enough financial incentive to continue development or production. The Orphan Drug Act incentivizes drug development for rare diseases.

What rare diseases are difficult to diagnose? ›

Huntington disease, ALS (Lou Gehrig disease), Tourette syndrome, and muscular dystrophy are among them.

What is an extremely rare genetic condition? ›

Rare genetic disorders include: AA amyloidosis. Adrenoleukodystrophy (ALD). Ehlers-Danlos syndrome.

Are rare diseases actually rare? ›

A rare disorder is a condition that affects fewer than 200,000 Americans. There are over 10,000 rare diseases that together affect more than 30 million Americans. NORD is dedicated to the identification, treatment, and cure of these diseases through comprehensive education, advocacy, research, and service programs.

Is a rare genetic disorder a disability? ›

When someone has a genetic variation, it means that something is a bit different in their DNA. Depending on which part of your DNA is affected, you may have a genetic variation that results in disability.

What is the best DNA test for rare diseases? ›

Whole-genome sequencing offers the highest likelihood of finding a diagnosis for rare genetic disease.

How long does it take to get a diagnosis for a rare disease? ›

The 'diagnostic odyssey' is a term used to describe the long and difficult journey that many rare disease patients and their families undertake to receive an accurate diagnosis – a journey that takes, on average, 5.6 years.

How accurate are genetic tests for diseases? ›

In general, most genetic tests are accurate when performed by reputable companies. However, the interpretation or meaning of test results can differ depending on who reports the results. Also, DTC genetic testing does not always provide useful information to help you make decisions about your health.

What percentage of all diseases are genetic? ›

The nature versus nurture debate remains one of the longest-running discussions among the scientific community.

Are rare diseases always genetic? ›

Many—but not all—rare diseases are genetic. Some are apparent at birth while others do not appear until much later in life. Approximately two-thirds of Americans with rare diseases are children.

Are 80 of rare diseases genetic in origin? ›

Around 80% of rare diseases are of genetic origin and the majority start in childhood. Everyone has the right to a timely diagnosis, as well as affordable treatment and care. We stay committed to leaving no one behind, no matter where they live, no matter their disease.

What percentage makes a disease rare? ›

In the United States, the Food and Drug Administration (FDA) defines a rare disease as any disease that affects fewer than 200,000 Americans. In Europe, a disease is defined as rare when it affects less than 1 in 2,000 people.

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