For families struggling to diagnose developmental disorders in their children, a new study may ultimately provide some answers. Clinical genetic testing of protein-coding regions identifies a likely causative variant in only around half of developmental disorder cases. But researchers in the UK found that mutations in non-coding regions of the DNA were also linked with these disorders. Published in a paper in the American Journal of Human Genetics, the team identified seven variants that cause developmental disorders that were previously unknown. Six of the genes were linked with the gene MEF2C — four single-nucleotide variants and two copy-number variants upstream of MEF2C in a total of ten individuals.
The findings are part of the U.K. Deciphering Developmental Disorders (DDD) study, which recruited children with undiagnosed developmental disorders between 2010-2015 to see if new genetic technologies can help doctors understand why patients get developmental disorders. For this analysis, the teams looked in regions of the genome that are immediately adjacent to protein-coding regions, known as untranslated regions, or UTRs. These regions are not coded into the final protein, but instead regulate processes; such as controlling how much protein is made, when it stops and where the protein ends up in the cell. Specifically, they screened mutations in the 5’ UTRs of genes which have previously revealed variants shown to cause developmental disabilities.
Through computational and lab-based methods, researchers identified that these six variants in the 5’ UTRs that impacted the gene MEF2C caused developmental disabilities through three loss of function mechanisms: either by changing the levels of gene expression, reducing the amount of protein produced or disrupting the function of the MEF2C protein.
“These non-coding region variants represent 23% of likely diagnoses identified in MEF2C in the DDD cohort, but these would all be missed in standard clinical genetics approaches,” the authors write. “Nonetheless, these variants are readily detectable in exome sequence data.”
“By looking at parts of the genome that are found next to protein coding regions, we have been able to identify multiple variants that cause developmental disorders that would have been missed by current clinical screening,” said Dr. Nicky Whiffin, senior author of the study and research Group Leader at the Wellcome Centre for Human Genetics, University of Oxford. “In fact, we found that nearly one quarter of diagnoses identified in the Deciphering Developmental Disorders study in one particular gene are due to non-coding region variants. While this this does not mean that one quarter of all developmental disease diagnoses are due to variants in non-coding regions, it suggests that it could be highly beneficial to analyze these regions in patients that remain genetically undiagnosed.”