A rare de novo contiguous 15q11.1-q13.3 duplication with tetrasomy (CN=4) and adjacent trisomy (CN=3) associated with severe global developmental delay, autism spectrum disorder, and subclinical epileptiform discharges: a case report and literature review
TL;DR
This case expands the genomic spectrum of complex proximal 15q rearrangements and highlights the value of high-resolution genomic testing for resolving complex neurodevelopmental disorders, and emphasizes that severe genetic etiologies may be overlooked when developmental abnormalities are initially attributed to prematurity.
Abstract
Background 15q11.2–q13 duplication syndrome (Dup15q; OMIM #608636) is a rare neurodevelopmental disorder. While interstitial duplications (copy number = 3) are relatively well characterized, contiguous rearrangements comprising both tetrasomic (copy number = 4) and adjacent trisomic (copy number = 3) segments are rare. We report a Chinese girl with a de novo contiguous 15q11.1–q13.3 duplication, whose underlying genetic diagnosis was initially delayed because her early neurodevelopmental abnormalities were partly attributed to prematurity. Case Presentation The patient was born at 35+2 weeks of gestation and presented with global developmental delay, severe autism spectrum disorder (CARS: 44), and profound cognitive and language impairment (GQ 30, GMQ 57 at 2 years 4 months). Brain MRI demonstrated delayed myelination, and magnetic resonance spectroscopy showed metabolic abnormalities in the left frontal lobe. Video-electroencephalography at 3 years of age revealed sleep-activated frontocentral epileptiform discharges without clinical seizures. Trio whole-genome sequencing with copy number variation analysis identified a de novo contiguous duplication consisting of a ∼10.34 Mb tetrasomic segment (15q11.1–q13.2; CN = 4) and an adjacent ∼2.40 Mb trisomic segment (15q13.2–q13.3; CN = 3). Despite long-term rehabilitation, the patient remained nonverbal and exhibited persistent severe neurodevelopmental impairment. Conclusion This case expands the genomic spectrum of complex proximal 15q rearrangements and highlights the value of high-resolution genomic testing for resolving complex neurodevelopmental disorders. It also emphasizes that severe genetic etiologies may be overlooked when developmental abnormalities are initially attributed to prematurity. These findings support early comprehensive genomic evaluation in children with profound developmental delay, autism spectrum disorder, or persistent developmental impairment despite conventional rehabilitation.