Genetic testing reveals key CNVs in affected children

Developmental delay and intellectual disability are common neurodevelopmental concerns in pediatrics and often present with a wide range of clinical features.¹ Establishing a genetic etiology supports diagnostic clarity and informed counseling. A study from the Changzhi Maternal and Child Health Care Hospital evaluated the role of copy number variations in these conditions using chromosomal microarray analysis and whole-exome sequencing.²

The study included 99 pediatric patients with developmental delay or intellectual disability. Ages ranged from 2 days to 33 years, and 61.6% were male. Developmental delay was documented in 67 patients, and intellectual disability in 62. Other clinical features included delayed speech, hypotonia, autism-related symptoms, seizures, and abnormal facies. A total of 82 patients underwent single-nucleotide polymorphism array testing, and 17 underwent whole-exome sequencing.^1,2

What CNVs were detected in this pediatric population?

Across the cohort, 43 copy number variations were identified in 40 children. Of these, 32 were clinically significant, yielding a diagnostic rate of 30.3%. Most were deletions (75%), followed by duplications (22%), and a single case of loss of heterozygosity (3%). Among variants with known inheritance status, 65.2% were de novo. The authors reported that “4 CNVs were maternally inherited” and “2 CNVs were paternally inherited,” underscoring varied inheritance mechanisms and the clinical value of parental testing.

Which recurrent CNV regions were most frequently identified?

Several recurrent regions known to be associated with neurodevelopmental disorders were observed.

• 15q11.2-q13.1: Identified in four patients, associated with developmental delay, intellectual disability, speech delay, and abnormal facies.
• 16p11.2: Found in two children, associated with intellectual disability, hyperactivity, or absent speech.
• 22q11.2: Identified in three cases and associated with craniofacial anomalies, asymmetric crying facies, and developmental delay.

These findings align with known associations reported in the literature and highlight the diagnostic value of chromosomal microarray analysis.

What rare or gene-specific CNVs were observed?

The study identified rare pathogenic variants involving SOX10 and SHANK3, each detected in two children. SOX10-related deletions were associated with hearing impairment, hypotonia, leukodystrophy, and semicircular canal abnormalities. SHANK3 deletions were linked to neurodevelopmental delay, language impairment, autism, and specific craniofacial features. One patient demonstrated combined deletions affecting both SOX10 and SHANK3, presenting with more complex manifestations, including hypoplasia of the corpus callosum and hearing impairment. The authors noted that such findings “suggest further investigation into gene interactions and their influence on neurodevelopmental outcomes.”

A case of loss of heterozygosity involving chromosome 2 was associated with a homozygous UNC80 variant. This genetic finding is consistent with infantile hypotonia with psychomotor retardation and characteristic facies, demonstrating the utility of integrating sequencing methodologies when chromosomal microarray results are inconclusive.

Why did some patients with clinical symptoms have normal CMA results?

Despite the presence of developmental delay or intellectual disability, 59.6% of patients had normal chromosomal microarray results. These children exhibited features such as hypotonia, autism traits, seizures, or speech delay. According to the study, “additional genetic factors…could play a role in the observed phenotypes,” including single-nucleotide variants, epigenetic changes, or environmental influences.

What challenges remain in interpreting CNVs and VOUS?

Variants of uncertain significance were found in 11 patients. These variants varied widely in size and involved genes linked to autosomal or X-linked recessive conditions, though phenotypic correlation was incomplete. The authors noted that interpretation is limited by available evidence and may evolve as genomic databases expand.

Study limitations included the single-center design, incomplete parental testing, challenges in interpreting VOUS, and the inability of chromosomal microarray analysis to detect balanced rearrangements or low-level mosaicism.

What are the clinical implications of CNV testing for pediatric developmental delay?

The study concludes that chromosomal microarray analysis “serves as an effective diagnostic tool” for pediatric developmental delay and intellectual disability. The authors emphasize the importance of family-based testing to clarify inheritance patterns and inform counseling. They note that future multi-omics approaches may improve the interpretation of uncertain variants and deepen the understanding of the genetic contributors to neurodevelopmental disorders.

References

1. Marrus, N., and Hall, L. (2017). Intellectual disability and language disorder. Child. Adolesc. Psychiatr. Clin. N. Am. 26, 539–554. doi:10.1016/j.chc.2017.03.001
2. Tao Y, Guo H, Han D, et al. Uncovering genetic contributors to developmental delay and intellectual disability: a focus on CNVs in pediatric patients. Frontiers in Genetics. 2025;16:1539902-1539902. doi:https://doi.org/10.3389/fgene.2025.1539902