Developmental Delays and Intellectual Disabilities in Children Often Linked to Genetic Causes

A thorough analysis conducted on over a thousand children with global developmental delay or intellectual disability reveals that nearly half of these cases originate from genetic anomalies. These disorders, which affect between 1.3% and 1.4% of children worldwide, manifest as delays in multiple areas of development such as motor skills, language, or social interactions before the age of five, or as intellectual and adaptive difficulties after this age.

The study shows that genetic tests, particularly trio whole-exome sequencing—which analyzes the DNA of the child and both parents—can identify the genetic cause in 48.1% of cases. This approach is more effective than tests performed solely on the child or targeted analyses of specific genes. The responsible genetic anomalies are primarily point mutations or copy number variations in certain genes.

The genes involved play a key role in essential biological processes such as protein balance, synapse and ion channel function, epigenetic regulation, or signaling pathways critical for development. For example, genes related to synapses are more frequent in children who also have epilepsy, while those associated with epigenetic regulation are often found in children with atypical facial features.

Among the most frequently affected genes are MECP2 and SYNGAP1, which are involved in brain development. Genetic variations can be inherited from parents or occur spontaneously. In some cases, these variations are present only in certain cells, a phenomenon called mosaicism, which can complicate diagnosis if tests are performed only on blood.

The results also highlight that girls have a higher rate of genetic diagnosis than boys, which could be explained by a greater tolerance in girls to genetic variations or mechanisms related to X chromosome inactivation. Additionally, children with facial malformations have a higher diagnosis rate, suggesting that these physical signs can be a useful indicator for guiding genetic testing.

Signaling pathways such as Ras-MAPK and PI3K-AKT-mTOR, known for their role in cell growth and differentiation, are also involved in these disorders. These pathways are shared with certain cancer mechanisms, but the genetic variations associated with developmental delays generally occur earlier in life and affect the developing brain differently.

This study underscores the importance of genetic testing to understand the causes of these disorders and pave the way for more tailored management. It also shows that some cases remain undiagnosed due to the limitations of current techniques, which do not always detect complex genetic variations or anomalies present only in certain tissues.

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Reference Document

DOI: https://doi.org/10.1007/s00431-026-07111-1

Title: Genetic testing and analysis of 1024 children with global developmental delay or intellectual disability: a single-center cohort study

Journal: European Journal of Pediatrics

Publisher: Springer Science and Business Media LLC

Authors: Bing Wang; Xinna Ji; Fan Wu; Mengyao Shen; Ping Zheng; Shuo Feng; Huanhuan Wu; Shupin Li; Aijie Liu; Lina Xie; Xue Zhang; Qian Chen