4 March 2020

After years of medical exploration, researchers from Radboud university medical center and their Swiss colleagues have found the cause of two rare conditions that cause intellectual disability with unusual facial features. The culprit? Errors in the SPOP gene. This gene is involved in breaking down multiple substances, and it therefore plays an important role in a variety of processes in cells. The first patients with these new syndromes have since been detected.

Initial indication

“In 2016, we found the first indications that SPOP played a role in the onset of intellectual disability”, explains Bert de Vries, a clinical geneticist in Radboud university medical center. “Using a new technique, we discovered a mutation in this gene in a 20-year-old woman with an intellectual disability. At that time, she was the only known patient in the world in whom this mutation had been detected. When there is only one patient with such a specific genetic abnormality, it is impossible to say with any certainty that the mutation is actually the cause of the intellectual impairment and developmental disorder.”
Within a year, De Vries was able to track down other patients from Utrecht, Sheffield and Chicago. Of these four patients, two had microcephaly (a skull circumference that is too small) and congenital hearing impairment. The other two had macrocephaly (a skull circumference that is too large) and normal hearing. What was going on? How could this be explained?

More or less active

De Vries came into contact with Dr Jean-Philippe Theurillat of the Institute of Oncology Research in Bellinzona, Switzerland. For years, Theurillat had been investigating the SPOP gene in cancer and had demonstrated that alterations in the gene could either strengthen or weaken its functioning. In adults, such changes can lead to various forms of cancer in proliferating body cells: prostate cancer and cervical cancer. The Swiss research group demonstrated that the functioning of the SPOP gene was strengthened in the patients with microcephaly, while it was weakened in the second group of patients with macrocephaly (which had since increased to include five patients). De Vries recounts, “It was a wonderful breakthrough and a fine confirmation that we were on the right track.”

Cause detected

“When we had a total of seven patients, we took another good look at the facial traits”, explains the physician-researcher Maria Nabais Sá. “As it turns out, the two patients with microcephaly looked exactly alike, and the other five also resembled each other as well. This was an unusual example of a single gene that had caused two different syndromes—it was a gene with two different faces.” We are seeing this more and more in the field of genetics. In addition to being strongly dependent on position within the gene, the effect of a mutation depends on the time at which the mutation occurs. A very early mutation in the SPOP gene upon fertilisation leads to developmental disorders and intellectual disabilities. If the mutation does not occur until adulthood, it can lead to certain types of cancer.

Further research

De Vries continues, “Whether the very early change in the SPOP gene also has an influence on a variety of cell types, and thus on multiple organs, is a component of the further research. At this time, patients who were born with this genetic abnormality do not appear to be at any greater risk of cancer, but we are following this closely. At any rate, we have now found an explanation for this very rare syndrome.” Sá adds, “For the patients involved, and for their parents, it can be quite a relief—finally knowing the cause of the condition.”
Publication in the American Journal of Human Genetics (AJHG): De Novo Variants in SPOP Cause Two Clinically Distinct Neurodevelopmental Disorders - Maria J. Nabais Sá, Geniver El Tekle, Arjan P.M. de Brouwer, Sarah L. Sawyer, Daniela del Gaudio, Michael J. Parker, Farah Kanani, Marie-José H. van den Boogaard, Koen van Gassen, Margot I. Van Allen, Klaas Wierenga, Gabriela Purcarin, Ellen Roy Elias, Amber Begtrup, Jennifer Keller-Ramey, Tiziano Bernasocchi, Laurens van de Wiel, Christian Gilissen, Hanka Venselaar, Rolph Pfundt, Lisenka E. L. M. Vissers, Jean-Philippe P. Theurillat, Bert B. A. de Vries 

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