With approximately 80% of rare diseases having a genetic basis, decoding as much of the human genome as possible is a constant effort, as better understanding can inform efforts to improve the treatment or management of these difficult conditions. Gleaning a better understanding of the human genome is especially critical when it comes to multisystem developmental disorders of unknown origin.
When faced with a group of 7 patients presenting with a similar disorder of unknown origin, researchers from Baylor College of Medicine were able to identify a potential genetic root to the condition. The patients shared a substantial overlap in condition characteristics, such as developmental delay, congenital heart defects, and limb and digital anomalies.
For their study, published in the American Journal of Human Genetics
and led by Xia Wang, MD, assistant professor of molecular and human genetics at Baylor College of Medicine and assistant laboratory director of Baylor Genetics, the team decided to sequence all the protein-coding genes in the patients' genomes. By doing so, they hoped to find a shared, underlying genetic basis, which, they did. They discovered 4 different mutations in the gene TRAF7
, which resulted in a reduction of the normal activity of a cellular pathway called ERK1/2.
"Our lab receives many samples for whole exome sequencing - the sequencing all the protein-coding genes—to try to identify the genetic cause of those patients' diseases," commented corresponding author Dr Wang, in a recent statement
. "When we analyzed the data of these patients, we did not find mutations in genes that are known to cause certain diseases, but we found mutations in the gene TRAF7
While Dr Wang clarified that gene mutations in a particular gene do not necessarily mean that they are the cause the disease, finding a way to determine whether the mutations can affect the relevant signaling pathways associated with the gene could shed light on disease origin.
, according to study authors, is a multi-functional protein that is involved in diverse signaling pathways as well as cellular processes.
Through clinical exome sequencing, missense variants in TRAF7
were identified. In 6 of the 7 patients, the identified variants were found to be de novo
and compromised 4 distinct missense changes, including a c.1964G>A (p.Arg655Gln) variant, which was recurrent in 4 patients. These variants are located in key functional domains and affect evolutionarily conserved amino acids. The phenotypic consequence of germline TRAF7
variants remains unclear.
Additionally, gene-specific mutation rate analysis suggests that the de novo
variants in TRAF7
(p = 2.6 × 10−3
) and the recurrent de novo
c.1964G>A (p.Arg655Gln) variant (p = 1.9 × 10−8
) in the exome cohort did not occur by chance.
Furthermore, reduced ERK1/2 phosphorylation was also observed in in vitro
analyses in TRAF7
mutations. "We conducted extensive functional assays and showed that the mutations we identified in these patients can reduce the function of the signaling pathway ERK1/2," added co-first author Chun-An Chen, research assistant in molecular and human genetics in the Christian Schaaf lab. "I am excited that advanced and unbiased sequencing technologies can help us find variants of genes that could be causing the disease."
Previous work has indicated that a group of diseases called RASopathy is associated with a change of function of the ERK1/2 pathway. RASopathy shares some features with the TRAF7
-related disorders like those studied in the 7 individuals, but further studies are needed to possibly establish a mechanistic link between the 2 groups of diseases.
Furthermore, previous studies have shown mutations in TRAF7
have also been observed in cancer tissue, according to Dr Wang. "One of the oldest patients in our cohort did have a meningioma,” he highlighted. “TRAF7
joins the growing list of genes that are implicated in both cancer and human developmental disorders."
Looking forward, the researchers plan to find more patients carrying variants in the TRAF7
gene who present with similar clinical characteristics. By studying them, they hope to better understand the connection of the TRAF7
gene to the multisystem disorder present in the 7 individuals examined. More research can help inform affected families and clinicians on what to expect in these children as they age.