Identified as part of the Undiagnosed Disease Program, the new disorder is caused by mutations in a gene involved in the regulation of fundamental components of cell membranes.
“A great national and international team effort”
That’s how Manuela Morleo, a researcher at the Telethon Institute of Genetics and Medicine (TIGEM) in Pozzuoli and at the University of Campania "Vanvitelli", describes the essential element that has led to the recent identification of a new neurodevelopmental disorder. The news of the discovery, which took place as part of the Undiagnosed Disease Program coordinated at TIGEM by Professor Vincenzo Nigro, was published in the American Journal of Human Genetics.
A new case for the Undiagnosed Disease Program
It was 2019 when the case of a seven-year-old girl with a complex clinical picture was brought to the attention of the program by geneticists at the Policlinico Gemelli in Rome. The clinical profile was characterized by microcephaly, intellectual disability, developmental delay, absent language, epilepsy, eye anomalies, and particular facial features. “All of these elements suggested a genetic cause due to the mutation of a single gene, but the investigations carried out up to that moment hadn’t been able to identify it,” says Morleo. This is where the Undiagnosed Disease Program came into play which, in Italy, has the role of identifying the cause of extremely rare and unknown diseases (that have remained undiagnosed for years). Twenty clinical centers are involved in the programme, including the Policlinico Gemelli. Program researchers carried out Next Generation Sequencing of the little patient's genome, in particular all the portions that code for proteins (the exome), searching for the anomaly that could account for her clinical picture.
Indeed, they found an anomaly, a mutation in a gene called PIP5K1C, never previously associated with any disease. This gene codes for an enzyme which has the task of regulating, through specific chemical modifications, the activity of a group of lipids which control the composition of cell and organelle membranes. "However, be careful! Finding a mutation in a gene in a single patient is not enough to establish a cause-effect relationship between the mutation and the clinical manifestations observed" explains Morleo.
A great team effort
The next step was to find the same or other mutations in the same gene in other patients with a similar clinical picture. "To do this - continues the researcher - we turned to national and international databases that report rare clinical features of patients together with any genetic variants identified in their genome". In this way, eight other patients were identified: some of them were Italians, others were from the United States, Canada, Europe, and Pakistan. They had the same clinical manifestations of the child reported by the Policlinico Gemelli and, importantly, they had the same mutations in the PIP5K1C gene. US researchers from the Undiagnosed Disease Program also collaborated in identifying these patients.
"At this point, the hypothesis about the involvement of the PIP5K1C gene had strengthened further " says Morleo, "but another test was still missing: the validation of the biological mechanism that could link the alteration of the gene to the disease". A validation in which the multidisciplinary expertise of TIGEM was fundamental. “Thanks to the collaboration with colleagues Rossella Venditti and Brunella Franco, we discovered that, in patient cells, the mutation of the PIP5K1C gene leads to the accumulation of lipids in vesicles (endosomes) which are used for the transport of molecules inside the cells and for their recycling. The consequence of the accumulation is a deterioration in the recycling capacity of the endosomes. This is associated with an alteration in the function of neurons, which has already been described for numerous neurodevelopmental disorders”. After that, a French colleague was able to generate a preclinical model with features resembling the clinical manifestations observed in patients.
“So we confirmed our hypothesis that we were dealing with a new genetic disease.”
This is not the first time that this has happened. “As part of the Undiagnosed Disease Program, we have identified at least 20 genes that are considered to be strong candidates associated with diseases that have never been described before and whose experimental validation is completed or still in progress, always in collaboration with other research groups in Italy and abroad”.
411 of the 830 cases analyzed were diagnosed thanks to this program, with a success rate close to 50%, higher than those obtained by similar programs in the United States or Great Britain. “A success” – concludes Morleo – “made possible thanks to the synergy among an entire group of researchers with different roles and skills, from doctors to geneticists, from bioinformatics to cell biologists, from technicians to researchers who interpret the DNA sequence".