Early childhood genetic testing for global developmental delay could reduce misdiagnosis rate

Early childhood genetic testing for global developmental delay could reduce misdiagnosis rate | Image Credit: © Cavan - © Cavan - stock.adobe.com.

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

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

Definitive biomarkers and treatment measures for GDD are lacking according to the investigative team, though genetic factors play a significant role in the pathogenesis of GDD. Appropriate genetic testing and comprehensive evaluations are “increasingly acknowledged as essential for comprehending the etiology of GDD and identifying innovative intervention strategies,” wrote the investigators. The measures are critical for effectively managing GDD and hope for improved neurodevelopmental outcomes.

Investigators sought to determine the implications of genetic testing for GDD in children, assess the utility of genetic detection in patients with GDD, and examine the potential molecular pathogenesis of GDD to identify targets of early intervention.

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

Genomic DNA was extracted from blood samples collected from patients and their parents. Gene Ontology (GO) enrichment analyses were conducted on the detected genes in the GDD cohort using R software. The primary outcomes of the study involved enhancing the rate of positive genetic diagnosis for GDD, expanding the scope of genetic testing indications, and investigating underlying pathogenesis. Levels of cognitive impairment were based on the developmental quotient assessed using the Gesell scale, wrote the study authors.

In all, the study featured 434 individuals with GDD with diverse degrees of cognitive impairment (60% male, mean age, 25.75 [13.24] months):

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

With the combined use of trio-WES and CNV-seq, investigators found a 61% positive detection rate, 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) being associated with a higher risk of carrying genetic variants.

Based on bioinformatics analysis, genetic variants may induce alteration in brain development and function, which could give rise to cognitive impairment, the study authors noted. “Moreover, an association was found between the dopaminergic pathway and cognitive impairment,” they wrote.

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

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

“We have identified an association among genetic variation, brain development, and clinical phenotype. Notably, our findings also suggest a positive correlation exists between dopaminergic synapse and GDD,” the investigative 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