Concurrent 12p trisomy and 4q34.2-q35.2 deletion detected by WES-CNV: Case report

Genetic diagnosis of developmental delay remains challenging, particularly in cases with a negative karyotype. Trisomy 12p syndrome is attributed to dosage effects of critical genes on chromosome 12p, such as KRAS and ETV6. Specifically, germline duplication of KRAS - a key regulator of the mitogen-activated protein kinase signaling pathway - can disrupt neurodevelopment and skeletogenesis, while duplication of ETV6 may alter its role in hematopoiesis and embryonic differentiation, contributing to the syndromic phenotype.

A 21-month-old boy presented with global developmental delay (GDD) as the primary concern.

Whole-exome sequencing detected a 35.8 Mb duplication on chromosome 12p concomitant with a 14.39 Mb deletion at 4q34.2-q35.2, leading to a diagnosis of concurrent 12p trisomy and 4q deletion syndromes.

The child exhibited severe craniofacial and upper limb deformities concomitant with GDD. A multidisciplinary symptomatic management plan was implemented, encompassing muscle strengthening exercises and structured language training. A custom dynamic forearm orthosis was prescribed to optimize functional limb positioning.

At follow-up, the patient has developed independent sitting ability and improved upper limb functional mobility, though no significant change in humeral length was observed.

This study delineates a unique case of dual, presumed de novo copy number variants - 12p trisomy and 4q deletion - exhibiting synergistic pathogenesis. The resulting phenotypic superposition, characterized by extreme brachymelia and GDD, was more severe than what is typically associated with either anomaly alone. The origin of these copy number variants, while presumed de novo, could also plausibly result from an unbalanced translocation, a key limitation of this study. This case establishes a novel model for understanding syndromic developmental delay in the context of a negative karyotype and validates the superior diagnostic capability of whole-exome sequencing-based copy number variant analysis in identifying complex genomic disorders.