The study, published in the journal Genetics in Medicine, analyzed the genomes of one thousand people with neurodevelopmental disorders
A research study carried out by the Medical Genetics Unit of IRCCS Istituto Giannina Gaslini in Genoa and the Center for Clinical and Computational Genomics (C3G) of the Istituto Italiano di Tecnologia (IIT-Italian Institute of Technology) in Aosta found a potential cause of motor and cognitive skill loss over time in people with neurodevelopmental disorders. The article was published in the journal Genetics in Medicine and highlights how errors in DNA repair lead to an accumulation of genetic variants and consequent skill regression.
Neurodevelopmental disorders encompass a broad category of conditions, including autism, various intellectual disabilities, and epilepsy. In some cases, individuals lose skills acquired during early years of life, such as reading and oral communication abilities. They show regression, rather than improvement, despite rehabilitation and educational programs. The research team investigated the molecular and biological causes of this regression by studying the DNA of over one thousand individuals using genome analysis.
“Our work suggests that developmental regression, observed in some patients with neurodevelopmental disorders, may be facilitated by the combination of alterations in multiple genes involved in DNA repair mechanisms,” explains Dr. Maria Cerminara, first co-author of the study and researcher at the Medical Genetics Unit of Gaslini Hospital. “These variants compromise genome stability and lead to an increase in somatic mutations and expansions of repeated sequences, phenomena that could directly contribute to neurodevelopmental regression.”
Among all the analysed cases, the research team focused on six patients who carry variants that can compromise DNA damage correction processes, thus causing cells to accumulate new damage and lose functionality. In this process, variants in DNA repair genes present from birth can lead to new deleterious mutations that, over time, contribute to the loss of skills acquired during development.
Among the genes considered, the research group focused on one, called FAN1, because it plays an important role in correcting certain genetic errors and is involved in other neurological pathologies.
“Thanks to different DNA sequencing techniques and advanced bioinformatics algorithms, we were able to precisely quantify the accumulation of variants in patients with cognitive regression,” explains Dr. Giovanni Spirito, first co-author and researcher at IIT in Aosta. “We observed that in one of the cases with variants in the FAN1 gene, genomic instability was so marked as to suggest an active and progressive mechanism during development. It’s a discovery that changes the way we think to the origins of these conditions.”
“These results indicate that genome instability, rather than being a marginal phenomenon, could represent a key element in understanding the most severe and regressive forms of neurodevelopmental disorders,” emphasizes Professor Aldamaria Puliti, project coordinator and Professor of Medical Genetics at Gaslini Hospital and at the DiNOGMI of the University of Genoa. “This new perspective opens new possibilities, both for diagnosis and for the future development of personalized therapies.”
“These results inaugurate an innovative research line to understand the molecular basis of neurodevelopmental disorders,” comments Professor Stefano Gustincich, study coordinator and director of the C3G at IIT in Aosta. “This work once again demonstrates the importance of multidisciplinary collaborations in addressing extremely complex conditions like these.”
The research falls within personalized and precision medicine, recognizing that each patient carries unique variants that lead to equally unique molecular alterations. Molecular-level knowledge of individuals with neurodevelopmental disorders enables more accurate diagnoses and personalized therapies. This approach requires cross-disciplinary expertise and close collaboration between clinical and research teams.
The Medical Genetics Unit of IRCCS Istituto Giannina Gaslini in Genova is directed by Professor Federico Zara; C3G at IIT is coordinated by Stefano Gustincich. The two groups collaborated with Fatebenefratelli Hospital in Milan and Beauregard Hospital in Aosta. The research was supported by funds from the NRRP, by the plan “Progetti di Rilevante Interesse Nazionale” of Italian Ministry of University and Research, by Italian Ministry of Health, by European Regional Development Fund and by European Social Fund.
