Researchers at the Institute of Human Genetics Göttingen have uncovered the genetic cause of a previously undescribed disorder associated with a combination of several malformations and intellectual disability. Surprisingly, their patients, three unrelated children, come from the same geographical region. Relatively little is known so far about the function of the identified gene, FBRSL1.

A study led by researchers of the Institute of Human Genetics at the University Medical Center Göttingen has uncovered the genetic cause of a new and complex syndromic disorder. Three children showed an overlapping clinical picture with a severe developmental delay, respiratory and swallowing problems, growth retardation, joint contractures, dysmorphic facial features and other malformations like heart defects. Two of the children had a particularly striking feature: distinctive skin creases, predominantly on the back, which were present at birth but decreased during the first year of life. This specific combination of features had not been described before. To find the underlying cause of the disorder and to provide the affected families with a precise diagnosis, the researchers performed exome sequencing. This molecular genetic tool allows to analyze in a single step all parts of a patient’s DNA that contain information required to make proteins. The researchers found that all three children carried a variant of the FBRSL1 gene. This gene and its encoded protein have so far not been investigated in detail.

“Usually, when we try to find a genetic defect that underlies an unclear disorder, we only have a single patient and his or her parents. If we find a candidate gene, the next step must then be to look for other patients who are similarly affected. This is quite challenging for a rare disorder which affects perhaps only a few patients across the globe”, says Professor Silke Pauli, research group leader at the Institute of Human Genetics Göttingen and senior co-author of the study. “Here, with three affected children, unrelated and coming from the same region, we have a rather unusual situation. It makes us assume that the disorder is not so very rare after all and might be present in more patients than previously appeared”.

To explore how the identified genetic changes affect cellular and molecular processes, the researchers performed various cell and animal experiments together with their collaboration partner Professor Annette Borchers and her team at the University Marburg. Their results suggest that a reduction in protein function during embryogenesis leads to a disturbance in neurodevelopment. In a project funded by the German Research Foundation (DFG), Professor Pauli and her team will now continue to gain deeper insights into the role of FBRSL1 in the development of the disease.

The study has been published in Human Genetics.