In a big breakthrough for parents with concerns about their child’s development, researchers have advanced the use of genetic testing to improve diagnosis for global developmental delay.
In the study, the combined use of trio-WES with CNV-seq in children with early-stage GDD resulted in a positive detection rate of 61% — an improvement of between 8 % to 40% — as well as reducing the number of missed diagnoses and further clarifying the indicators used for detection.
Lead author Dr Changlian Shu, from the Institute of Neuroscience and Physiology at the University of Gothenburg, said the new approach not only saved time for families but also reduced the economic costs that would have been incurred through trying different testing methods.
“Moreover, the combination of trio-WES and CNV-seq testing addressed the limitations of each method, leading to a more comprehensive genetic analysis and a reduction in missed diagnoses,” he said.
“Despite the clinical heterogeneity of GDD phenotypes, strict adherence to indications for genetic testing is crucial to avoid unnecessary medical interventions. However, due to technological constraints, trio-WES may miss 55% of CNV variations, whereas CNV-seq has a missed diagnosis rate of 3%.
Similarly, CNV-seq cannot detect SNVs or indels and as such, there currently exists a lack of clarity among health care professionals regarding the necessity of genetic testing – even though previous studies have indicated a correlation between positive genetic testing rates and factors such as family history, male sex, and number of phenotypes.
“In our study, we have further refined the indications for testing, establishing that patients aged 12 to 24 months and those with moderate or higher cognitive impairment, craniofacial abnormalities, or complex phenotypes are more likely candidates for genetic testing,” Dr Shu said.
“The precise mechanisms by which the genome influences cognitive function and brain development are still under investigation, with many genes associated with GDD predominantly expressed in early life to impact the development of the nervous system.”
The study found that genes such as SYNGAP1, GRIN2B, GRIN1, DLG4, SCN2A, ADNP, MECP2, and EP300 all contributed to abnormal brain development and function, elucidating the core symptoms of GDD.
The predominant nature of all CNV segments was characterised by deletions, including within the15q11.2-q13.1 region, commonly associated with Angelman syndrome and Prader-Willi syndrome, emerging as the most prevalent.
The dopaminergic synapse emerged as the second most crucial pathway associated with GDD and cognitive impairment, substantiated by prior research and animal models.
“Therefore, targeting the dopaminergic pathway holds promise for treating GDD and ID, although further comprehensive research is needed to confirm the efficacy of this approach,” Dr Shu concluded.