Early childhood genetic testing for global developmental delay may reduce misdiagnosis rates

Early childhood genetic testing for global developmental delay may reduce misdiagnosis rate | Image credit: © Cavan – © Cavan – stock.adobe.com.

Investigators of a recent study published in JAMA Network Open determined that early use of combined genetic testing for global developmental delay (GDD) “can reduce misdiagnosis rates, clarify etiologic diagnosis, and lay the groundwork for identifying new early diagnostic biomarkers and intervention targets” .

GDD is a neurodevelopmental disorder marked by cognitive impairment. Intellectual disability (ID) develops in most children with GDD after age 5, affecting physical abilities, social functioning, and quality of life. ID ranks among the top 10 global diseases, with an overall prevalence rate of approximately 1%.

According to the research group, definitive biomarkers and treatment measures for GDD are lacking, although genetic factors play an important role in the pathogenesis of GDD. Appropriate genetic testing and comprehensive evaluations are “increasingly asserted as essential to understanding the etiology of GDD and identifying innovative intervention strategies,” the investigators write. Measures are critical to the effective management of GDD and hope for improved neurodevelopmental outcomes.

The investigators sought to determine the implications of genetic testing for GDD in children, evaluate the utility of genetic screening in patients with GDD, and examine the potential molecular pathogenesis of GDD to identify targets for early intervention.

The multicenter, prospective cohort study enrolled patients aged 12 to 60 months with GDD from 6 centers in China. Enrollment was conducted from July 4, 2020 to August 31, 2023. Participants underwent trio exome sequencing (trio-WES), paired with copy number variation sequencing (CNV-seq). Bioinformatics analysis was used to “uncover pathogenesis and identify therapeutic targets,” the study authors noted.

Genomic DNA was extracted from blood samples collected from the patients and their parents. Gene Ontology (GO) enrichment analyzes were performed on the genes detected in the GDD cohort using R software. The main results of the study included increasing the rate of positive genetic diagnosis for GDD, expanding the scope of genetic testing indications, and investigating the pathogenesis basic. Levels of cognitive impairment were based on developmental quotients assessed using the Gesell scale, the study authors wrote.

Overall, the study included 434 individuals with GDD with varying degrees of cognitive impairment (60% male, mean age, 25.75 [13.24] month):

• Mild: 93 patients (23%)
• Moderate: 141 patients (32%)
• Severe: 122 patients (28%)
• Advanced: 73 patients (17%)

With the combined use of trio-WES and CNV-seq, the investigators found a positive detection rate of 61%, with craniofacial abnormalities (odds ratio [OR], 2.27; 95% CI, 1.45-3.56), moderate or severe cognitive impairment (OR, 1.69; 95% CI, 1.05-2.70), and age between 12 and 24 months (OR, 1 .57; 95% CI, 1.05-2.35) with a higher risk of carrying genetic variants.

Based on bioinformatics analysis, genetic variants can cause changes in brain development and function, which can cause cognitive impairment, the study authors noted. “Furthermore, a link was found between the dopaminergic pathway and cognitive impairment,” they wrote.

The findings are based on an early childhood GDD cohort, a limitation of the study that warrants caution when extrapolating results to other populations. Potential differences may exist between clinical phenotypes collected in the cohort and those in national or global GDD cohorts, another limitation of the study. The study included “only” a subset of patients with GDD for detection of plasma dopamine. An expansion of the sample size and the performance of in vivo and in vitro experiments are necessary steps to verify whether dopamine can be targeted for medical intervention with clinical accuracy in patients with GDD.

Overall, the study findings support the clinical utility of combining trio-WES sequencing with CNV-seq in the etiologic diagnosis and management of GDD in early childhood.

“We have identified a link between genetic variation, brain development and clinical phenotype. Notably, our findings also suggest that there is a positive correlation between the dopaminergic synapse and GDD,” the research team concluded.

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