The human genome is composed of 20,000 genes and as of today, 3,200 of these genes are known to cause diseases, of which 1,700 are associated with ‘recessive’ diseases. Recessive diseases only occur when both the father and the mother are healthy carriers of the same defective gene which can be passed down to their children. Now, researchers from the University of Geneva (UNIGE) and University of Osaka have identified a previously unknown recessive disease resulting from the failure of a single gene which combines intellectual disability, epilepsy and hypotonia. The team state that by identifying the gene responsible for the onset of this disease, they have opened the door to specialized diagnostics and prevention. The opensource study is published in The American Journal of Human Genetics.
Previous studies show that with an estimated prevalence of approximately 1%, intellectual disability is one of the most common disorders of the human population. Different definitions are available, however, the general consensus is that the IQ should be below 70 and symptoms should appear during the development period. Intellectual disability has several etiologies, and its genetic causes, including chromosomal aneuploidies, copy-number variants, and monogenic disorders, are estimated to account for 25%–50% of all cases. To find the cause of a specific intellectual disability with hypotonia and epilepsy the lab looked into the cases of consanguineous families, because the probability of suffering from a recessive disease is then higher, since both parents must carry the same genetic defect. There is, therefore, a higher chance of identifying a gene responsible for this syndrome by studying the members of an affected consanguineous family. The current study identifies the cause of this disorder by sequencing the genomes of families presenting these symptoms, and identifies the responsible gene, namely PIGG.
The current study investigated families in which several members presented intellectual disability with hypotonia and epilepsy. Results using genome sequencing, identified one gene which likely caused this intellectual disability. The group explain that this gene, known as PIGG, is an important element in the protein production chain. They go on to add that its role is to encode an enzyme that processes the modification of other proteins. Data findings show that when it dysfunctions, it prevents some of these proteins from being processed normally, causing intellectual disability, epilepsy, and hypotonia, which characterizes this syndrome.
The team still needed to confirm that it caused the disease once the gene was identified. They entered PIGG into an international database, known as Matchmaker, in order to see if other researchers had also noticed this gene’s involvement in people with similar symptoms. They gained a positive answer and conducted in vitro experiments on the gene’s biochemistry, which allowed them to confirm its role in provoking the disease.
The team surmise that their findings are significant for the research and prevention of recessive genetic diseases. They go on to add that potential defects in the PIGG gene can be detected by sequencing patients from consanguineous families or any family and this analysis can even be performed prenatally. For the future, the researchers state as precision genetic diagnosis becomes possible, this disease will be identified among other people presenting the same symptoms, also paving the way for new treatments.
Source: University of Geneva (UNIGE)