Genetic Testing Offers Hope for Early Diagnosis of Global Developmental Delay in Childhood: Study

The cohort study of 434 children with GDD suggests that early use of combined genetic testing may diminish the misdiagnosis rate, elucidate the etiologic diagnosis, and lay the groundwork to identify novel early diagnostic biomarkers and intervention targets. The findings were published online in JAMA Network Open on June 5, 2024. 

Global Developmental Delay, characterized by significant delays in multiple areas of development such as cognition, language, motor skills, and socialization, poses substantial challenges for affected individuals and their families. While early detection and intervention are crucial for maximizing developmental potential, diagnosing GDD can often be complex and time-consuming, relying on clinical assessments and evaluations.

Cognitive impairment is the core symptom, and despite the pivotal role of genetic factors in the development of GDD, the understanding of them remains limited. To fill this knowledge gap, Jiamei Zhang, Third Affiliated Hospital of Zhengzhou University, Zhengzhou, China, and colleagues aimed to assess the utility of genetic detection in patients with GDD and to examine the potential molecular pathogenesis of GDD to identify targets for early intervention.

For this purpose, the researchers conducted a multicenter, prospective cohort study enrolling patients aged 12 to 60 months with GDD from 6 centers in China from 2020 to 2023. Participants underwent trio whole exome sequencing (trio-WES) and copy number variation sequencing (CNV-seq). Bioinformatics analysis was used to unravel pathogenesis and identify therapeutic targets.

The study's main outcomes involved enhancing the positive genetic diagnosis rate for GDD, broadening the scope of genetic test indications, and investigating the underlying pathogenesis. The classification of children into cognitive impairment levels was based on the developmental quotient evaluated using the Gesell scale.

The following were the key findings of the study:

• The study encompassed 434 patients with GDD (60% male; mean age, 25.75 months) with diverse degrees of cognitive impairment: mild (23%), moderate (32%), severe (28%), and profound (17%).
• The combined trio-WES and CNV-seq resulted in a 61% positive detection rate.
• Craniofacial abnormalities (odds ratio [OR], 2.27), moderate or severe cognitive impairment (OR, 1.69), and age between 12 and 24 months (OR, 1.57) were associated with a higher risk of carrying genetic variants.
• Bioinformatics analysis suggested that genetic variants may induce alterations in brain development and function, which may give rise to cognitive impairment.
• There was an association between the dopaminergic pathway and cognitive impairment.

The study supports the clinical utility of trio-WES sequencing with CNV-seq combined in the etiologic diagnosis and clinical management of early childhood GDD.

"We have identified an association among genetic variation, brain development, and clinical phenotype. Notably, our findings suggest a positive correlation between dopaminergic synapse and GDD," the researchers wrote.

Reference:

Zhang J, Xu Y, Liu Y, et al. Genetic Testing for Global Developmental Delay in Early Childhood. JAMA Netw Open. 2024;7(6):e2415084. doi:10.1001/jamanetworkopen.2024.15084