How do I prevent genetic disabilities

50 new genetic causes of intellectual disability discovered

Genetic defects that affect only one gene lead to intellectual disabilities and related disorders

For more than 15 years, genome research has focused on the search for common genetic risk factors of common diseases such as diabetes, high blood pressure, schizophrenia and cancer, largely without success. One of the reasons for this is that many different genetic disorders can be concealed behind these clinical pictures, and it is not uncommon for them to be defects in individual genes. Most of these genetic defects, however, have not yet been clarified. Researchers at the Max Planck Institute for Molecular Genetics in Berlin and their colleagues from Iran have now succeeded in identifying 50 previously unknown genetic causes of intellectual disability. There is good reason to believe that several of these new genetic defects are also responsible for related disorders such as autism, schizophrenia, or epilepsy.

To date, nearly 7,000 'monogenic' diseases are known, and the gene defect in question has already been identified for about half of them. They are found in around 17 percent of all children admitted to hospitals. Their share in the total costs of health care is significantly higher. However, many monogenic diseases are still unknown. They are often not diagnosed because they are cases without a recognizable familial accumulation or because they are patients with supposedly complex widespread diseases.

An international consortium with significant participation from the Max Planck Institute for Molecular Genetics has now discovered 50 previously unknown genetic causes of intellectual disability in children. This disorder only occurs if the - usually healthy - parents have a predisposition for a certain genetic defect and if both of them pass on a mutated copy of the same gene to their children. So far, very little is known about such 'recessive' genetic defects, because the scientists needed families with several affected people - that is, large families, if possible - to clarify the situation.

Such families are rare in Germany and other western countries, but not in populations of the Near and Middle East. In addition, many parents are related in these countries, which could be the reason why intellectual disabilities are about three times more common there than in our country. Therefore, the Max Planck researchers worked closely with a research center in Iran. We all have genetic defects in us. But for blood relatives, the risk is much greater that these are the same genetic defects, ”says Hilger Ropers. Sick children of blood relatives carry two identical copies of the responsible genetic defect, but the surrounding chromosome segments are also completely the same. This made it easier for the researchers to find the defective gene.

Since the start of the cooperation in 2003, more than a thousand predominantly Iranian families with disabled children have been called in for examinations. In 136 of these families, the researchers were able to localize the defect in the genome with sufficient accuracy and identify it in 78 using new sequencing techniques.

In addition to mutations in 22 already known disease genes, the German-Iranian research team found noticeable changes in 50 other genes. With a few exceptions, these genes can be assigned to known regulatory signaling pathways. Many products of the conspicuously altered genes interact directly with other proteins in these networks, which are encoded by already known genes for intellectual disability. “This is a direct indication that the genes we found are actually responsible for the disability,” says Ropers.

Surprisingly, the majority of these genes and gene products are not only active in the human brain, but also in other organs. The researchers suspect that this could be related to a particular susceptibility of the brain to disorders of cellular metabolism and other basic cellular functions, which can be traced back to the enormous complexity of the central nervous system. Ongoing studies on animal models are expected to provide the definitive proof that the gene mutations found influence brain function.

These studies, published online in the English journal Nature, confirm the enormous genetic diversity of intellectual disabilities and divide them into different monogenic defects, which in most cases are limited to individual families. "Our findings will help to significantly shorten the often years-long search by affected families for a reliable diagnosis and open up new possibilities for family planning", says Hilger Ropers.

Furthermore, these studies are a model for the elucidation of related disorders such as autism, schizophrenia and epilepsy, but also for many other complex diseases with a genetic background, for which genome-wide association studies have been largely unsuccessful. There is evidence that such disorders and intellectual disability are often related. About 30 percent of all people with intellectual disabilities also suffer from epilepsy, and as many as 70 to 80 percent of all autistic people are also mentally disabled. The results of these investigations are therefore also of great importance for the elucidation of these complex diseases.